Hitta Ko Na Ulit Ulit Aut Me a Tout

Home , Betamethasone benzoate, Medrysone

HITTA KO NAULITUS 20180112180A1 ULIT AUTME A TOUT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0112180 A1 Robbins et al. (43 ) Pub . Date : Apr. 26 , 2018 (54 ) CELLS WITH INCREASED Publication Classification IMMUNO -REGULATORY PROPERTIES AND METHODS FOR THEIR USE AND (51 ) Int. CI. MANUFACTURE C12N 5 /0789 ( 2006 .01 ) CO7K 14 / 705 ( 2006 . 01) ( 71) Applicant: Fate Therapeutics, Inc ., San Diego , C12N 9 / 02 ( 2006 .01 ) CA (US ) A61K 35 /28 ( 2006 .01 ) A61K 38 / 17 ( 2006 .01 ) ( 72 ) Inventors : David Robbins, San Diego, CA (US ) ; A61K 38 /44 ( 2006 .01 ) Betsy Rezner , San Diego , CA (US ); A61P 37 /00 ( 2006 .01 ) Leah Mitchell , San Diego , CA (US ) ; A61P 29 /00 (2006 .01 ) Lisa Guerrettaz , San Diego , CA (US ); (52 ) U . S . Cl. Philippe Alessandro Parone, San CPC ...... C12N 5 / 0647 ( 2013. 01 ) ; CO7K 14 / 70532 Diego , CA (US ) ; Robert Steven Tacke , (2013 .01 ) ; C12N 9 /0069 (2013 . 01 ) ; C12Y San Diego , CA (US ) ; Kevin Lai, San 113 / 11052 ( 2013 .01 ) ; A61K 35 /28 ( 2013 .01 ) ; Diego , CA (US ); Bahram Valamehr , A61K 2035 / 124 ( 2013 . 01 ) ; A61K 38 / 44 San Diego , CA (US ) (2013 .01 ) ; A61P 37/ 00 ( 2018 .01 ) ; A61P 29/ 00 ( 2018 . 01 ) ; C12N 2501 /02 ( 2013 .01 ) ; C12N (21 ) Appl . No. : 15 /546 , 255 2501/ 999 ( 2013. 01 ); A61K 38 / 1774 (2013 .01 ) ( 22 ) PCT Filed : Jan . 26 , 2016 ( 86 ) PCT No. : PCT/ US2016 / 014942 (57 ) ABSTRACT $ 371 (c )( 1 ), ( 2 ) Date : Jul. 25 , 2017 The present invention is directed to compositions and meth ods to increase the expression of PD -L1 and / or IDO - 1 in a Related U . S . Application Data population of cells , the modulated cells expressing increased (60 ) Provisional application No . 62/ 107 ,517 , filed on Jan . PD - L1 and / or IDO - 1 , and methods related to the immuno 26 , 2015 , provisional application No. 62 / 112 ,653 , suppressive effects obtained by cells expressing increased filed on Feb . 6 , 2015 . PD -L1 and / or IDO - 1 . Patent Application Publication Apr . 26 , 2018 Sheet 1 of 15 US 2018 /0112180 A1

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FIG . 6 Patent Application Publication Apr . 26 , 2018 Sheet 10 of 15 US 2018 /0112180 A1

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FIG . 12 US 2018 /0112180 A1 Apr. 26 , 2018

CELLS WITH INCREASED [0006 ] Thus, what is needed in the art is a method for IMMUNO - REGULATORY PROPERTIES AND producing HSPCs having increased PD -L1 and /or IDO - 1 METHODS FOR THEIR USE AND expression without exposing the cells to the stress of in vitro MANUFACTURE processes and prolonged cell culture . [ 0007 ] The invention addresses these limitations through CROSS -REFERENCE TO RELATED the identification of a number of molecules or compounds APPLICATIONS which , in a short - term incubation , independently or in combination , pharmacologically up - regulate PD -L1 and / or [0001 ] This application claims the benefit under 35 U . S . C . IDO - 1 expression on cells , including HSPCs. $ 119 ( e ) of U . S . Provisional Application No . 62 / 107 ,517 filed Jan . 26 , 2015 and U . S . Provisional Application No. BRIEF SUMMARY OF THE INVENTION 62 / 112 ,653 filed on Feb . 6 , 2015 which are each herein [0008 ] The present disclosure provides compositions and incorporated by reference in their entireties . methods to modulate the immune system through the immuno -regulatory properties of cells expressing increased BACKGROUND levels of programmed death ligand 1 ( PD -L1 ) and indoleam ine 2 , 3 - dioxygenase 1 ( IDO - 1 ) . The present disclosure is [0002 ] Uncontrolled immune activation can be lethal, and directed to compositions and methods to increase the expres so the immune system is tightly regulated , in part by sion of PD -L1 and /or IDO -1 in a population of cells , the pathways responsive to inflammation that modify immune modulated cells expressing increased PD -L1 and /or IDO - 1 , cell functions. and methods related to the immunosuppressive effects 10003 ] PD -L1 , also known as B7 -H1 , is a transmembrane obtained by cells expressing increased PD - L1 and / or IDO - 1 . protein that belongs to the B7 family of T cell co - inhibitory [0009 ] A first object of the invention includes methods for molecules . The binding of PD -L1 to its receptor PD - 1 modulating a population of cells comprising : incubating the dampens T cell activation , decreases proliferation and cyto population of cells in the presence of one or more exogenous toxicity , and induces apoptosis . The immuno - regulatory agents capable of increasing PD -L1 and / or IDO - 1 expres property ofhematopoietic stem and progenitor cells (HSPC ) sion to obtain a population of cells having increased expres is enhanced upon increased expression of PD -L1 . PD -L1 has sion of PD -L1 and / or IDO - 1 . been described in cancer immunotherapy for its role in [0010 ] In one aspect, the incubation is in vitro or ex vivo . blocking T cell activation and proliferation . More specifi [0011 ] In one aspect, the incubation is between about 5 cally , PD -L1 is capable of preventing T cell activation minutes to about 72 hours. In a further aspect, the incubation through competition for costimulatory molecules on the T is between about 4 hours to about 48 hours . cell ( e . g . B7- 1 and / or B7 - 2 ) and through direct engagement [0012 ] In one aspect , the incubation is performed at a of PD1 on the T cell. Therefore , PD -L1 is capable of temperature of between about 4° C . to about 37° C . In a regulating T- cell activation in a cell contact dependent further aspect, the incubation is performed at a temperature fashion .Moreover , the therapeutic potential of HSPC -based of about 37° C . immunotherapies appears to be limited by the inherently low [0013 ] In one aspect the increase in PD -L1 and /or IDO - 1 expression levels of PD - L1 . expression in the modulated cells is at least 3 - fold . In one [0004 ] While increased levels of PD - L1 on HSPCs have aspect, the increase in PD -L1 and /or IDO - 1 is about 3 - fold been observed after culturing ex vivo , prolonged culture to about 80 - fold compared to cells not incubated with the periods can result in replicative stress, stochastic cellular exogenous agent. defects , and chromosomal abnormalities. [0014 ] In one aspect, the exogenous agent( s ) are selected [0005 ] IDO - 1 ( indoleamine 2 , 3 -dioxygenase ) is an from one or more polynucleotides , one or more polypep enzyme which catalyzes the degradation of the essential tides , one or more small molecules , and combinations amino acid tryptophan ( TRP ). The depletion of tryptophan thereof. In one aspect, the polypeptide is an interferon in the microenvironment halts T -cell proliferation , induces receptor agonist. In a further aspect, the interferon receptor TH1 cell apoptosis, and activates regulatory T cells . This agonist is selected from IFN - a , IFN - B , IFN - II , IFN -K , method of immune suppression is also naturally used by IFN - W , IFN - y , or a combination thereof. In a particular many other immunosuppressive cells , and is also used by aspect, the population of cells is modulated with IFN -B and many tumors to escape immune- activation . Although IDO IFN - y . enzymes are intracellular and not secreted , the metabolic [0015 ] In yet another aspect, the polynucleotide is selected effects of IDO - 1 initially provide local effect, as neighboring from poly (I : C ), a polynucleotide encoding PD -L1 and /or a cells respond to the reduced access to TRP. However , as the polynucleotide encoding IDO -1 . microenvironment is depleted of TRP, cells in proximity , but [0016 ] In one particular aspect , at least two, at least three , not in contact with the IDO - 1 expressing cell are affected . or more exogenous agents are administered . In a particular Thus, in an autoimmune situation IDO - 1 prevents T cell aspect, IFN - B , IFN - y , and poly ( I : C ) are administered . activation and proliferation by depleting TRP from the [0017 ] In one aspect , the polynucleotide is selected from inflammatory microenvironment , and activates regulatory T poly ( I: C ), a polynucleotide encoding PD -L1 and /or a poly cell suppression of the immune response . Expression of nucleotide encoding IDO - 1 . IDO - 1 is very low in hematopoietic stem or progenitor cells [0018 ] In one aspect , the small molecules comprise glu under normal conditions . Thus , modulation of IDO - 1 levels cocorticoids , prostaglandin pathway agonists antineoplas in hematopoietic stem and progenitor cells provides an tics , dopamine receptor agonists , isometheptene mucate, opportunity to affect the immuno - regulatory properties of dihydrostreptomycin sulfate , protriptyline, telenzepine, those cells , and upon administration , the immunological cyclobenzaprine, 4 - aminosalicylic acid and combinations properties of patients ' cells . thereof. In one aspect , the prostaglandin pathway agonist is US 2018 /0112180 A1 Apr. 26 , 2018

selected from PGE2, dmPGE2, 15 ( S ) - 15 -methyl PGE2, [0027 ] A second object of the invention includes a popu 20 -ethyl PGE2, 8 - iso - 16 - cyclohexyl- tetranor PGE2, 16 , 16 lation of cells having increased PD - L1 and /or IDO - 1 expres dimethyl PGE2 (“ dmPGE2 " ) , p -( p -acetamidobenzamido ) sion obtained by the methods described in the first aspect phenyl ester, 11- deoxy - 16 , 16 - dimethyl PGE2, 9 - deoxy - 9 and aspects thereof . methylene - 16 , 16 - dimethyl PGE2, 9 -deoxy - 9 -methylene [ 0028 ] Athird object of the invention includes a method of PGE2, 9 -keto Fluprostenol, 5 - trans PGE2, 17 -phenyl treating an immunological disorder comprising : administer omega - trinor PGE2, PGE2 serinol amide , PGE , methyl ester, ing a therapeutically effective amount of the population of 16 -phenyl tetranor PGE2, 15 (S )- 15 -methyl PGE2, 15 (R ) - 15 cells obtained by the methods described in any of the methyl PGE2, 8 - iso - 15 - keto PGE2, 8 - iso PGE, isopropyl embodiments and / or aspects above to a patient in need ester , 8 - iso - 16 - cyclohexyl- tetranor PGE2, 20 -hydroxy thereof. PGE2, 20 - ethyl PGE2, 11- deoxy PGE1, nocloprost, sulpro [0029 ] In one aspect, the population of cells comprises stone, butaprost , 15 -keto PGE2, and 19 (R ) hydroxy PGE2. hematopoietic cells . In one aspect , the population of [0019 ] In one aspect , the glucocorticoid is selected from hematopoietic cells is derived from cord blood , peripheral medrysone , alclometasone , alclometasone dipropionate , blood , bone marrow , or iPSCs . amcinonide , beclometasone , beclomethasone dipropionate , [ 0030 ] In yet a further aspect , the population of cells betamethasone , betamethasone benzoate , betamethasone comprises HSPCs. valerate , budesonide, ciclesonide , clobetasol, clobetasol [0031 ] In a further aspect, the population of cells com butyrate , clobetasol propionate , clobetasone , clocortolone , prises at least about 50 % , at least about 50 % , at least about cloprednol, cortisol, cortisone , cortivazol, deflazacort , des 60 % , at least about 70 % , at least about 80 % , at least about onide , desoximetasone, desoxycortone, desoxymethasone , 85 % , at least about 90 % , at least about 95 % , at least about dexamethasone, diflorasone , diflorasone diacetate , diflucor 98 % , or at least about 99 % HSPCs . In a particular aspect , the tolone , diflucortolone valerate , difluorocortolone, diflupred population of cells comprises a substantially pure population nate , fluclorolone, fluclorolone acetonide , fludroxycortide , of HSPCs . flumetasone , flumethasone , flumethasone pivalate, flunisol [0032 ] In yet a further aspect , the population of cells is ide , flunisolide hemihydrate , fluocinolone , fluocinolone enriched for CD34 + HPSCs prior to contact with the exog acetonide, fluocinonide , fluocortin , fluocoritin butyl , fluo enous agent. cortolone , fluorocortisone, fluorometholone , fluperolone , [ 0033 ] In one aspect, the population of cells is allogeneic fluprednidene , fluprednidene acetate, fluprednisolone , fluti to the patient. In a further aspect , the population of cells is casone , fluticasone propionate, formocortal , halcinonide , HLA matched with the patient. In yet a further aspect, the halometasone , hydrocortisone , hydrocortisone acetate , population of cells comprises haplotyped enhanced -HSPCs . hydrocortisone aceponate , hydrocortisone buteprate , hydro In another aspect, the population of cells is partially HLA cortisone butyrate , loteprednol, meprednisone, 6a -methyl matched or unmatched with the patient. prednisolone , methylprednisolone , methylprednisolone [0034 ] In one aspect, the therapeutically effective amount acetate , methylprednisolone aceponate , mometasone , of the population of cells comprises about 2x10 $ to about mometasone furoate , mometasone furoate monohydrate , 2x101° CD34 + hematopoietic cells . paramethasone, prednicarbate , prednisolone , prednisone , [0035 ]. In one aspect, the method comprises more than one prednylidene, rimexolone, tixocortol, triamcinolone , triam administration of a therapeutically effective amount of cells . cinolone acetonide and ulobetasol , as well as combinations In one aspect, the frequency of administrations ranges from thereof. In a further aspect, the glucocorticoid is selected about every other week to about every six months. In a from betamethasone , clobetasol proprionate , flumethasone, further aspect , the initial administration is a higher number flucinolone acetonide, medrysone , hydrocortisone, triamci of cells than a subsequent administration . nolone , alclometasone , and dexamethasone . 10036 ] In one embodiment, the immunological disorder is [0020 ] In one aspect, the antineoplastics are selected from an autoimmune disorder selected from acute myocardial gemcitabine, letrozole , and fludarabine and the dopamine infarction , ischemic stroke , type 1 diabetes, diabetes melli receptor antagonist is fluphernazine. tus , multiple sclerosis , acute disseminated encephalomyeli [ 0021 ] In one aspect, the population of cells comprises tis , inflammatory demyelinating diseases , lupus , Crohn ' s hematopoietic cells . disease , osteoarthritis , rheumatoid arthritis , psoriatic arthri [ 0022 ] In one aspect, the population of cells is isolated . In tis , ulcerative colitis , dermatitis , irritable bowel syndrome, a particular aspect, the population of hematopoietic cells is vitiligo , Graves' disease , Hashimoto ' s disease , Addison ' s derived from cord blood , peripheral blood , bone marrow , or disease , polymyositis , dermatomyositis , myasthenia gravis , autoimmune hepatitis , Sjögren ' s syndrome, autoimmune induced pluripotent stem cells (iPSCs ) . gastritis , sclerosis , psoriasis , asthma, or Wegener' s granu [0023 ] In another aspect, the population of hematopoietic lomatosis . cells is obtained from iPSCs . [0037 ] In a particular aspect , the immunological disorder [0024 ] In one aspect, the population comprises hematopoi is graft vs host disease or transplant rejection . In a further etic stem / progenitor cells (HSPCs ). aspect, the transplant rejections arose from a bone marrow [0025 ] In one aspect, the population comprises at least transplant, solid organ transplant, or cell therapy ( e . g . any about 50 % , at least about 60 % , at least about 70 % , at least composition comprising isolated stem cells ) . about 80 % , at least about 85 % , at least about 90 % , at least [0038 ] In one aspect, the patienthas undergone at least one about 95 % , at least about 98 % , or at least about 99 % HSPCs. ofhigh - dose , reduced - intensity , or nonmyeloablative condi In one aspect, the population comprises a substantially pure tioning . In one aspect, the patient has not undergone at least population of HSPCs. one of high -dose , reduced - intensity , or nonmyeloablative [ 0026 ] In one aspect , the population of cells is enriched for conditioning . In yet a further aspect , the patient has not CD34 + HPSCs prior to contact with the exogenous agent . undergone conditioning . US 2018 /0112180 A1 Apr. 26 , 2018

[0039 ] In one aspect, the patient is not a candidate for photoallergic dermatitis , phototoxic dermatitis , phytophoto cellular transplant or has not received a transplant . dermatitis , radiation dermatitis , and stasis dermatitis ), [ 0040 ] A fourth object of the invention includes methods scleroderma, ulcers and erosions resulting from trauma, of treating inflammation in a patient comprising : adminis burns, bullous disorders , or ischemia of the skin or mucous tering a therapeutically effective amount of the population of membranes, several forms of ichthyoses, epidermolysis cells obtained by the methods described in any of the bullosae , hypertrophic scars , keloids, cutaneous changes of embodiments and/ or aspects above to a patient in need intrinsic aging , photoaging , frictional blistering caused by thereof. mechanical shearing of the skin , cutaneous atrophy resulting [0041 ] In one aspect, the population of cells comprises from the topical use of corticosteroids, cheilitis , chapped hematopoietic cells . lips , nasal irritation , mucositis and vulvovaginitis . [0042 ] In one aspect , the population of hematopoietic cells [0055 ] In one aspect, the inflammation of the endocrine is derived from cord blood , peripheral blood , bone marrow , system is selected from autoimmune thyroiditis ( Hashimo or iPSCs. In a particular aspect, the population comprises to ' s disease ) , Type I diabetes , Type II diabetes, and acute and HSPCs. chronic inflammation of the adrenal cortex . 0043] In one aspect , the population comprises at least [0056 ] In one aspect, the inflammation of the cardiovas about 50 % HPSCs, at least about 50 % , at least about 60 % , cular system are selected from coronary infarct damage , at least about 70 % , at least about 80 % , at least about 85 % , peripheral vascular disease , myocarditis , vasculitis , revas at least about 90 % , at least about 95 % , at least about 98 % , cularization of stenosis , artherosclerosis , and vascular dis or at least about 99 % HSPCs. In a further aspect, the ease associated with Type II diabetes . population comprises a substantially pure population of [0057 ] In one aspect, the inflammation of the kidney is HSPCs. selected from glomerulonephritis , interstitial nephritis , lupus [0044 ] In one aspect, the population is enriched for CD34 + nephritis , nephritis secondary to Wegener' s disease , acute HPSCs prior to contact with the exogenous agent . renal failure secondary to acute nephritis , Goodpasture ' s [0045 ] In a further aspect , the population of cells is syndrome, post- obstructive syndrome and tubular ischemia . allogeneic to the patient. [ 0058 ] In one aspect, the inflammation of the liver is [0046 ] In one aspect, the population of cells is HLA selected from hepatitis ( arising from viral infection , auto matched with the patient. In another aspect, the population immune responses, drug treatments , toxins , environmental of cells is partially HLA matched or unmatched with the agents , or as a secondary consequence of a primary disor patient. In a further aspect , the population of cells comprises der) , biliary atresia , primary biliary cirrhosis and primary haplotyped enhanced -HSPCs . sclerosing cholangitis . [0047 ] In one aspect, the therapeutically effective amount 10059 ]. In one aspect, the inflammation of the central of the population of cells comprises about 2x100 cells to nervous system is selected from multiple sclerosis and about 2x1010 CD34 + hematopoietic cells . neurodegenerative diseases such as Alzheimer ' s disease , [0048 ] In one aspect , the method comprises more than one Parkinson ' s disease , or dementia associated with HIV infec administration of a therapeutically effective amount of cells . tion . In a further aspect, the frequency of administrations ranges [0060 ] In one aspect , the administration is systemic . In from about every other week to about every six months . In another aspect , the administration is local . one aspect, the initial administration is a higher number of [0061 ] In one aspect , the administration is intravenous, cells than a subsequent administration . intraarterial, intramuscular, intrathecal, intracapsular , intra [ 0049 ] In one aspect, the inflammatory disorder is selected orbital , intracardiac , intradermal, intraperitoneal, transtra from inflammation of the lungs , joints, connective tissue, cheal , subcutaneous ( subdermal ), subcuticular, intraarticu eyes , nose , bowel, kidney , liver, skin , central nervous sys lar, subcapsular, subarachnoid , intraspinal, intrastemal tem , endocrine system , cardiovascular system and heart. [ 0050 ] In one aspect, the inflammation of the lung is injection , or by infusion . selected from asthma, adult respiratory distress syndrome, [0062 ] In one aspect, the method is part of a combination bronchitis , pulmonary inflammation , pulmonary fibrosis , therapy . and cystic fibrosis . [ 0063 ] A fifth object of the invention includes a pharma 10051] In one aspect, the inflammation of the joints is ceutical composition comprising a population of modulated selected from rheumatoid arthritis , rheumatoid spondylitis , hematopoietic cells that expresses an increased level of juvenile rheumatoid arthritis , osteoarthritis , gouty arthritis PD -L1 and /or IDO - 1 expression that is about 3 fold to about and other arthritic conditions. 80 fold compared to a level of PD - L1 and /or IDO - 1 expres [ 0052 ] In one aspect, the inflammation of the eye is sion in a population of non -modulated hematopoietic cells . selected from uveitis ( including iritis ) , conjunctivitis , scleri [0064 ] In one aspect, the pharmaceutical composition fur tis , keratoconjunctivitis sicca , and retinal diseases , includ ther comprises a pharmaceutically acceptable carrier. ing, but not limited to , diabetic retinopathy, retinopathy of [0065 ] In one aspect , population of hematopoietic cells is prematurity , retinitis pigmentosa, and dry and wet age derived from cord blood , peripheral blood , bone marrow , or related macular degeneration . iPSCs. [0053 ] In one aspect, the inflammation of the bowels is [0066 ] In a particular aspect, the population of hematopoi selected from Crohn ' s disease , ulcerative colitis and distal etic cells is derived from differentiated iPSCs . proctitis . [0067 ] In one aspect, the population comprises HSPCs. In [0054 ] In one aspect, the inflammation of the skin is a further aspect , the population comprises at least about 50 % selected from psoriasis , eczema and dermatitis , ( e . g ., HPSCs , at least about 50 % , at least about 60 % , at least about eczematous dermatitides , topic and seborrheic dermatitis , 70 % , at least about 80 % , at least about 85 % , at least about allergic or irritant contact dermatitis , eczema craquelee , 90 % , at least about 95 % , at least about 98 % , or at least about US 2018 /0112180 A1 Apr. 26 , 2018

99 % HSPCs. In yet a further aspect, the population of DETAILED DESCRIPTION hematopoietic cells comprises a substantially pure popula [0085 ] I. Definitions tion of HSPCs . [0086 ] The articles “ a , ” “ an ,” and “ the ” are used herein to [0068 ] In one aspect , the population is enriched for CD34 + refer to one or to more than one ( i . e . , to at least one ) of the HPSCs. grammatical object of the article . By way of example , " an [ 0069 ] In one aspect, the composition is formulated for element” means one element or more than one element. intravenous administration , intraarterial administration , [0087 ] The use of the alternative ( e . g ., “ or” ) should be intramuscular administration , intrathecal administration , understood to mean either one, both , or any combination intracapsular administration , intraorbital administration , thereof of the alternatives . intracardiac administration , intradermal administration , [0088 ] As used herein , the term “ about” or “ approxi intraperitoneal administration , transtracheal administration , mately ” refers to a quantity , level, value, number , frequency, subcutaneous ( subdermal administration , subcuticular percentage , dimension , size , amount, weight or length that administration , intraarticular administration , subcapsular varies by as much as 15 % , 10 % , 9 % , 8 % , 7 % , 6 % , 5 % , 4 % , administration , subarachnoid administration , intraspinal 3 % , 2 % or 1 % to a reference quantity , level , value , number , administration , intrastemal administration , and infusion . frequency , percentage , dimension , size , amount, weight or [0070 ] In one aspect, the pharmaceutical composition is length . In one embodiment , the term “ about” or “ approxi formulated for a local or non -intravenous administration . mately ” refers a range of quantity, level, value , number, 10071 ] In one aspect, the population of cells comprises frequency , percentage, dimension , size , amount, weight or about 2x10 to about 2x101° CD34 + hematopoietic cells . length 15 % , + 10 % , + 9 % , 18 % , 17 % , 16 % , 25 % , + 4 % , [ 0072 ] A sixth object of the invention includes a kit + 3 % , 2 % , or + 1 % about a reference quantity , level , value, comprising the modulated cells obtained from the first object number, frequency, percentage, dimension , size, amount, of the invention or a pharmaceutical composition according weight or length . to the fifth object of the invention and a second active agent [0089 ] As used herein , the term “ substantially ” refers to a for use in a combination therapy . quantity , level , value , number , frequency, percentage , dimension , size , amount, weight or length that is 90 % , 92 % , BRIEF DESCRIPTION OF THE DRAWINGS 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or higher of a reference quantity , level, value, number , frequency , percent [0073 ] FIGS. 1A - 1E show gene expression following the age , dimension , size , amount , weight or length . In one modulation of hematopoietic stem and progenitor cells for embodiment, “ substantially the same” refers to a quantity , increased PD -L1 expression . level, value, number, frequency, percentage , dimension , [0074 ] FIGS. 2A - 2D show PD - L1 surface expression on size , amount, weight or length that produces an effect , e . g ., hematopoietic stem and progenitor cells following modula a physiological effect , that is approximately the same as a tion for increased PD -L1 expression . reference quantity , level, value , number, frequency , percent [0075 ] FIG . 3 shows T cell proliferation in the presence of age , dimension , size , amount , weight or length . HSC with modulated PD -L1 expression . [0090 ] As used herein , the terms “ substantially free of” [0076 ] FIG . 4 shows gene expression following the modu and “ essentially free of” are used interchangeably , and when lation of hematopoietic stem and progenitor cells for used to describe a composition , such as a cell population or increased PD - L1 expression . culture media , refer to a composition that is free of a [ 0077 ] FIGS . 5A - D show IDO - 1 gene expression levels in specified substance , such as , 95 % free , 96 % free , 97 % free , hematopoietic stem and progenitor cells following modula 98 % free , 99 % free of the specified substance , or is unde tion for increased IDO - 1 expression . tectable as measured by conventionalmeans . In one embodi 10078 ] FIG . 6 shows modulation for 24 hours at 37° C . ment, “ substantially pure” may be used to denote that the with additional exogenous agents for increased IDO - 1 composition or component is substantially free of contami expression . nants , such as other cell types . Similar meaning can be [0079 ] FIG . 7 shows PD - L1 surface expression applied to the term “ absence of, ” where referring to the hematopoietic stem and progenitor cells following modula absence of a particular substance or component of a com tion for increased PD - L1 expression for 6 , 24 , or 48 hours . position . [0080 ] FIG . 8 demonstrates that post- modulation , the [0091 ] Reference throughout this specification to " one modulated cells are viable and express PD -L1 at the cell embodiment, " " an embodiment, " " a particular embodi ment, " " a related embodiment, " " a certain embodiment, " surface when maintained in a variety of conditions . " an additional embodiment, ” or “ a further embodiment” or [0081 ] FIGS. 9A and 9B demonstrate that ex vivo treated combinations thereof means that a particular feature , struc human stem and progenitor cells suppress the proliferation ture or characteristic described in connection with the of both autologous and allogeneic T cells . embodiment is included in at least one embodiment of the 10082 ] FIG . 10 demonstrates that genetic overexpression present invention . Thus, the appearances of the foregoing of PD - L1 in human CD34 + stem and progenitor cells phrases in various places throughout this specification are enhances suppression of T cell proliferation . not necessarily all referring to the same embodiment. Fur [0083 ] FIG . 11 demonstrates that genetic overexpression thermore , the particular features, structures, or characteris of IDO - 1 in human CD34 + stem and progenitor cells tics may be combined in any suitable manner in one or more enhances suppression of T cell proliferation . embodiments . [0084 ] FIG . 12 shows that T cells treated with media from [0092 ] Throughout this specification , unless the context a modulated population of hematopoietic cells demonstrat requires otherwise , the words “ comprise ” , “ comprises ” and ing upregulated IDO - 1 expression significantly suppressed " comprising ” will be understood to imply the inclusion of a T cell proliferation . stated step or element or group of steps or elements but not US 2018 /0112180 A1 Apr. 26 , 2018 the exclusion of any other step or element or group of steps such as by administering cells with therapeutic potential one or elements . As used herein , the terms “ include” and “ com - or more times to a living subject. Both local and systemic prise ” are used synonymously . administration is contemplated for these embodiments , [0093 ] By “ consisting of” is meant including, and limited according to well -known techniques in the art and as to , whatever follows the phrase " consisting of. ” Thus, the described elsewhere herein . The amount of therapeutic cells phrase " consisting of” indicates that the listed elements are administered to a subject will depend on the characteristics required or mandatory , and that no other elements may be of that subject , such as general health , age , sex , body weight, present . and tolerance to drugs, as well as the degree , severity , and [0094 ] By “ consisting essentially of” is meant including type of reaction to the drug and /or cell transplant. any elements listed after the phrase , and limited to other [0099 ] As used herein , the term “ incubating " is used to elements that do not interfere with or contribute to the describe a specific step or steps by which cells or popula activity or action specified in the disclosure for the listed tions of cells are manipulated . Incubation steps may include elements. Thus , the phrase " consisting essentially of” indi specific temperatures, agents, or conditions which modulate cates that the listed elements are required or mandatory , but the cell or populations of cells . that no other elements are optional and may or may not be [0100 ] As used herein , the term “ exogenous” is used present depending upon whether or not they affect the interchangeably with the term " heterologous ” refer to a activity or action of the listed elements . substance coming from some source other than its native [0095 ] The term “ ex vivo ” refers generally to activities source . For example , the terms “ exogenous protein , " or that take place outside an organism , such as experimentation " exogenous cell ” refer to a protein or cell from a non - native or measurements done in or on living tissue in an artificial source or location , and that have been artificially supplied to environment outside the organism , preferably with mini a biological system . In contrast , the terms “ endogenous mum alteration of the natural conditions . In particular protein ,” or “ endogenous cell ” refer to a protein or cell that embodiments , " ex vivo " procedures involve living cells or are native to the biological system , species or individual. tissues taken from an organism and cultured or modulated in 10101 ] The phrase " stem cell ” as used herein refers to a a laboratory apparatus , usually under sterile conditions , and cell which is an undifferentiated cell capable of (1 ) long term typically for a few hours or up to about 24 hours , but self- renewal , or the ability to generate at least one identical including up to 48 or 72 hours , depending on the circum copy of the original cell, ( 2 ) differentiation at the single cell stances . In certain embodiments , such tissues or cells can be level into multiple , and in some instance only one , special collected and frozen , and later thawed for ex vivo treatment. ized cell type and ( 3 ) of in vivo functional regeneration of In one embodiment, the ex vivo modulation is for at least tissues . Stem cells are subclassified according to their devel about 1 hour, at least about 2 hours , at least about 3 hours , opmental potential as totipotent , pluripotent, multipotent at least about 4 hours , at least about 5 hours, at least about and oligo /unipotent . A progenitor cell” also has the capac 6 hours , at least about 7 hours , at least about 8 hours , at least ity to self -renew and to differentiate into more mature cells , about 9 hours , at least about 12 hours , at least about 18 but is committed to a lineage ( e . g . , hematopoietic progeni hours, at least about 24 hours , or at least about 36 hours . In tors are committed to the blood lineage ; myeloid progenitors one embodiment, the ex vivo modulation is for a time period are committed to themyeloid lineage ; lymphoid progenitors ranging from time period ranging from about 1 hour to about are committed to the lymphoid lineage ), whereas stem cells 72 hours , about 2 hours to about 48 hours , about 4 hours to are not necessarily so limited . “ Self - renewal” refers a cell about 48 hours , about 6 hours to about 48 hours , about 12 with a unique capacity to produce unaltered daughter cells hours to about 48 hours , about 1 hour to about 24 hours , and therefore replenish and maintain its population numbers , about 2 hours to about 24 hours , about 4 hours to about 24 and to generate specialized cell types (potency ). Self -re hours , about 6 hours to about 24 hours , about 12 hours to newal can be achieved in two ways . Asymmetric cell divi about 24 hours , about 1 hour to about 12 hours , about 4 sion produces one daughter cell that is identical to the hours to about 12 hours , about 6 hours to about 12 hours , or parental cell and one daughter cell that is different from the about 8 hours to about 12 hours . Tissue culture experiments parental cell and is a more committed progenitor or differ or procedures lasting longer than a few days using living entiated cell . Symmetric cell division produces two identical cells or tissue are typically considered to be “ in vitro ,” daughter cells . “ Proliferation ” or “ expansion " of cells refers though in certain embodiments , this term can be used to symmetrically dividing cells . interchangeably with ex vivo . [0102 ] As used herein , the term “ progenitor” or “ progeni [0096 ] The term “ in vivo ” refers generally to activities that tor cells ” refers to cells that have the capacity to self - renew take place inside an organism . and to differentiate into more mature cells . Progenitor cells [0097 ] The recitations “ ex vivo administration ," " ex vivo have a reduced potency compared to pluripotent and mul treatment, " or " ex vivo modulation , " relate generally to tipotent stem cells . Many progenitor cells differentiate along medical procedures in which one or more organs, cells , or a single lineage , but may also have quite extensive prolif tissues are obtained from a living or recently deceased erative capacity . subject, optionally purified / enriched , exposed to a treatment [0103 ] As used herein , the term “ hematopoietic stem and or procedure ( e . g . , an ex vivo administration step that progenitor cell” or “ HSPC ” refers to a cell identified by the involves incubating the cells with a composition or agent of presence of the antigenic marker CD34 (CD34 + ) and are the present invention to enhance engraftment of particular therefore characterized as CD34 + cells , and populations of cells , such as hematopoietic stem or progenitor cells ). Cells such cells . In particular embodiments , the term “ HSPC ” treated ex vivo may be administered to the donor or to a refers to a cell identified by the presence of the antigenic different living subject . marker CD34 (CD34 + ) and the absence of lineage (Lin ) [ 0098 ] Such ex vivo therapeutic applications may also markers and are therefore characterized as CD34 + /Lin ( - ) include an optional in vivo treatment or procedural step , cells , and populations of such cells . It is recognized that the US 2018 /0112180 A1 Apr. 26 , 2018 population of cells comprising CD34 + and /or Lin ( - ) cells ( including all integers and decimal points in between and also includes hematopoietic progenitor cells . The term above 1 , e . g ., 1 . 5 , 1 . 6 , 1 . 7 . 1 . 8 , etc .) the response produced “ hematopoietic cell ” refers to a continuum of cells ranging by vehicle ( the absence of an agent) or a control composi from a HSPC , to a fully differentiated blood cell , including tion . all the cells of the myeloid and lymphoid lineages . 10111 ] The terms " decrease ," " lower, " " lessen ," " reduce , " [0104 ] As used herein , the term " induced pluripotent stem and “ abate ” refer generally to the ability of an agent to cells ” or, iPSCs, means that the stem cells are produced from produce or cause a lesser physiological response ( i . e . , down differentiated adult , neonatal or fetal cells that have been stream effects ) in a cell , as compared to the response caused induced or changed , i. e ., reprogrammed into cells capable of by either vehicle or a control molecule / composition . A differentiating into tissues of all three germ or dermal layers : “ decreased ” or “ reduced ” amount is typically a “ statistically mesoderm , endoderm , and ectoderm . The iPSCs produced significant” amount, and may include an decrease that is 1 . 1 , do not refer to cells as they are found in nature . 1 . 2 , 1 . 5 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 15 , 20 , 30 or more times [0105 ] As used herein , a “ non - contacted , ” “ non - treated , " ( e . g . , 500 , 1000 times ) ( including all integers and decimal or an “ untreated ” cell is a cell that has not been treated , e . g . , points in between and above 1 , e .g . , 1 . 5, 1. 6 , 1 .7 , 1 .8 , etc .) cultured , contacted , or incubated with an agent other than a the response produced by vehicle (the absence of an agent ) control agent . Cells contacted with DMSO ( a control agent ) , or a control composition . or contacted with another vehicle are non -contacted cells . 10112 ] The “ therapeutic potential” of a cell refers to the [0106 ] As used herein , the term “ isolated ” refers to mate therapeutic quality of the cell , the cell ' s ability to provide a rial that is removed from its original environment . For therapeutic benefit when administered to a subject. In par example , an “ isolated population of cells ," an " isolated ticular embodiments , the therapeutic potential of a cell can source of cells , " or " isolated HSPCs” and the like , as used be measured , quantified , determined , identified , or validated herein , refer to in vitro or ex vivo separation of one or more by increased expression of PD - L1 and /or IDO - 1 . Therapeu cells from their natural cellular environment, and from tic potential includes , but is not limited to , a cell ' s ability to association with other components of the tissue or organ , inhibit an immune response in a subject. i . e ., it is not significantly associated with in vivo substances. [0113 ] The term “ gene” means the segment of DNA [0107 ] As used herein , the terms “ agent, ” and “ exogenous involved in producing a polypeptide chain ; it includes agent, ” are used interchangeably to refer to a compound or regions preceding and following the coding region ( leader molecule capable of increasing expression of PD -L1 and / or and trailer ) as well as intervening sequences ( introns) IDO - 1 in a cell that is contacted with the agent . between individual coding segments (exons ). [0108 ] As used herein , the term “ subject” refers to any [0114 ] “ Gene expression , ” or “ expression ," as used herein animal, preferably a human patient, livestock , or other refers to the transcription of a gene in the production of RNA domesticated animal. ( e . g ., mRNA , rRNA , TRNA , miRNA , or snRNA ), as well as 10109 ] As used herein , the terms “ treatment, ” “ treating, ” the translation of an mRNA in the production of a protein , and the like, refer to obtaining a desired pharmacologic or the relative levels of the translated product of a tran and / or physiologic effect, including without limitation scribed gene. Gene expression and / or the pattern of expres achieving an improvement or elimination of symptoms of a sion of a gene may be detected in a biological sample , such disease . The effect may be prophylactic in terms of com as hematopoietic cells , stem and progenitor cells , or a pletely or partially preventing a disease or symptom thereof population of cells comprising stem or progenitor cells , and / or may be therapeutic in terms of achieving an improve including, but not limited to , hematopoietic stem and pro ment or elimination of symptoms, or providing a partial or genitor cells . complete cure for a disease and /or adverse effect attributable to the disease. “ Treatment, ” as used herein , covers any [0115 ] An “ expression vector” is a nucleic acid construct , treatment of a disease in a mammal, particularly in a human , generated recombinantly or synthetically , with a series of and includes : ( a ) preventing the disease from occurring in a specified nucleic acid elements that permit transcription of a subject which may be predisposed to the disease but has not particular nucleic acid in a host cell . The expression vector yet been diagnosed as having it ; (b ) inhibiting the disease , can be part of a plasmid , virus, or nucleic acid fragment. i .e . , arresting its development; (c ) relieving the disease , e. g ., Typically , the expression vector includes a nucleic acid to be causing regression of the disease , e . g . , to completely or transcribed operably linked to a promoter. partially eliminate symptoms of the disease ; and ( d ) restor [0116 ] The term “ PD -L1 ” refers to programmed death ing the individual to a pre- disease state , e . g ., reconstituting ligand 1 , the 40 kDa type 1 transmembrane protein that is the hematopoietic system . encoded by the CD274 gene. PD -L1 binds to its receptor, [ 0110 ] The terms “ enhance ," " promote, " " increase ” and PD - 1 , found on activated T cells , B cells , and myeloid cells . " activate ” refer generally to the ability of an agent to PD -L1 is also known as “ CD274 ,” “ B7 homolog 1, ” and produce or cause a greater physiological response ( i . e . , “ B7- H1 . ” downstream effects ) in a cell , as compared to the response [0117 ] “ IDO - 1 ” refers to indoleamine 2 , 3 - dioxygenase , caused by either vehicle or a control molecule /composition , the 46 kDA enzyme catalyzing the oxidative catabolism of e . g . , increased PD -L1 and/ or IDO - 1 expression in a cell , the essential amino acid tryptophan ( TRP ) and producing such as for example , a hematopoietic stem and progenitor kynurenine (KYN ) pathway metabolites . cell. A measurable physiological response may include an [0118 ] The term “modulate , ” or “modulation ,” as used increase in the ability of a cell to modulate an immune herein refers to a change in the cells ' physiological status or response in a subject. An “ increased " or " enhanced ” amount modify or alter the properties of a cell . For instance , increas is typically a “ statistically significant” amount, and may ing the expression of a desired target gene, such as PD -L1 include an increase that is 1 . 1 , 1 . 2 , 1 . 5 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , and /or IDO - 1 , or increasing or decreasing an immune 10 , 15 , 20 , 30 or more times ( e .g . , 500 , 1000 times ) response from a cell . US 2018 /0112180 A1 Apr. 26 , 2018

[0119 ] II . Cell Modulation [0125 ] Suitable methods for determining the level of gene [ 0120 ] The invention provides compositions and methods expression in a sample include, but are not limited to , to modulate the immune system through the immuno - regu nucleic acid amplification , for example , by RT -PCR ( U . S . latory properties of cells expressing increased levels of Pat . No . 4 ,683 , 202) , ligase chain reaction (Barany , Proc . programmed death ligand 1 ( PD -L1 ) and indoleamine 2 , 3 Natl . Acad . Sci. USA 88 : 189 - 93 , 1991 ) , self -sustained dioxygenase 1 ( IDO - 1 ) . The invention generally relates to sequence replication (Guatelli et al ., Proc . Natl. Acad . Sci. methods and compositions for modulating cells with exog USA 87 : 1874 -78 , 1990 ), transcriptional amplification sys enous agents to achieve an increase in PD -L1 and / or IDO - 1 tem (Kwoh et al. , Proc . Natl . Acad . Sci. USA 86 :1173 - 77 , expression in the cells . The invention also relates to cells 1989 ) , Q -Beta Replicase (Lizardi et al. , Bio / Technology having increased PD -L1 and / or IDO - 1 expression , and 6 : 1197 , 1988 ) , rolling circle replication ( U . S . Pat. No . methods of using such cells in the therapeutic applications , 5 ,854 ,033 ), or any other nucleic acid amplification method , including the treatment of immunological disorders and followed by the detection of the amplified molecules using inflammation . techniques well known to those of skill in the art . [ 0121 ] Some aspects of the invention relate to the condi [0126 ] As used herein , the terms" conditions sufficient, " or tions for modulating a cell to achieve an increase in PD -L1 " under conditions sufficient, ” refer to the conditions for and / or IDO - 1 expression . In some embodiments , such con treating cells with one or more agents to increase PD -L1 ditions comprise contacting the cell with one or more and / or IDO - 1 expression in the cells to surprising and exogenous agents capable of increasing PD -L1 and / or unexpected levels compared to control, vehicle , or non IDO - 1 expression in the cell. In one embodiment, the cell is treated cells . Conditions include, but are not limited to the contacted with at least two or at least three exogenous agents used to treat the cells and concentrations of agent( s ) , agents . the time the cells are exposed to the agent( s ) , and the [ 0122 ] Such contact may occur, for example , by incubat temperature of treatment . ing the cell in the presence of one or more exogenous agents 0127 ]. A . Modulating Agents capable of increasing PD -L1 and /or IDO - 1 expression in the (0128 ] An aspect of the invention relates to the agents that cell . Conditions for contacting the cell may occur in vitro or are used to modulate cells for increased PD - L1 expression . ex vivo , such as under standard culture conditions, for Such agents include , but are not limited to , polynucleotides, example . polypeptides , small molecules , or a combination thereof. 10123 ] Another aspect of the invention relates to the time Small molecules for modulating cells include, but are not period during which the cell is contacted with the one or limited to , glucocorticoids and/ or prostaglandin pathway more agents capable of increasing PD -L1 and / or IDO - 1 agonists antineoplastics, dopamine receptor agonists and expression . In some embodiments , the cell is contacted with other agents . the one or more agents for a time of between about 5 minutes [ 0129 ] i . Peptides to about 96 hours . In other embodiments , the cell is con [0130 ] a . Interferon Receptor Agonists tacted with the one or more agents for about 1 hour, about [0131 ] In some aspects of the invention , cells are modu 2 hours , about 3 hours , about 5 hours , about 10 hours , about lated by being contacted with one or more interferon recep 24 hours , about 48 hours , about 96 hours , or any time period tor agonists . Suitable interferon receptor agonists for use intervening these specifically referenced times . In one with the invention include , but are not limited to , any embodiment, the cell is contacted for about four hours to naturally occurring or non - naturally occurring ligand of about 48 hours . In some aspects of the invention , the cell is Type I, Type II or Type III interferon receptors, which binds expanded in the presence of one or more agents capable of to and causes signal transduction via the receptor. Such increasing PD -L1 and /or IDO - 1 expression . Another aspect interferon receptor agonists include interferons, including of the invention relates to the temperature at which the cell naturally - occurring interferons , modified interferons , syn is modulated with the at least one exogenous agent. Accord thetic interferons, pegylated interferons , fusion proteins ingly , the cell may be modulated at any temperature that comprising an interferon and a heterologous protein , results in an increase in the expression of PD - L1 and /or shuffled interferons , an antibody or antibodies specific for an IDO - 1 in the cell. In some non - limiting embodiments of the interferon receptor, non -peptide chemical agonists , and the invention , the cell is modulated at a temperature of between like. about 4° C . to about 37° C . In one embodiment , the cell is [0132 ] In some aspects of the invention , the interferon modulated at about 37° C . receptor agonist comprises an interferon selected from the [0124 ] One aspect of the invention relates to the quanti group consisting of IFN -a , IFN - B , IFN - E, IFN -K , IFN - w , tative increase in PD -L1 and /or IDO - 1 expression in the IFN - y , or a combination thereof. In one non - limiting cells that results from being modulated with one or more embodiment of the invention , cells are modulated with agents capable of increasing PD -L1 and / or IDO - 1 expres IFN - B . In another non - limiting embodiment of the inven sion . It is contemplated that such increase may be about tion , the cells are modulated with IFN - y . In yet another 10 % , about 20 % , about 30 % , about 40 % , about 50 % , about embodiment, the cells are modulated with IFN - B and IFN - y . 60 % , about 70 % , about 80 % , about 90 % , about 100 % , about [0133 ] b . Polynucleotides Encoding Peptides 150 % , about 200 % or more, than the cells prior to treatment. [0134 ] In some aspects of the invention , cells are modu In particular embodiments , cells having increased PD -L1 lated with a polynucleotide comprising poly ( I : C ) . Poly and / or IDO - 1 expression have been modulated under con ( 1 : C ) , also known as polyinosinic polycytidylic acid , is a ditions sufficient to increase PD - L1 and /or IDO - 1 expression synthetic double - stranded RNA consisting of a strand of at least 2 , 3 , 5 , 10 , 20 , 30 , 40 , 50 , 60 , 70 , or 80 fold or more polyriboinosinic acid (Poly I) and a strand of polyribocyti in the modulated cells compared to control cells . Such dylic acid ( Poly C ) . Poly ( I : C ) is known to interact with increases may relate to an increase in gene expression , or an toll - like receptor 3 ( TLR3 ) which is expressed in the mem increase in protein expression . brane of B - cells, macrophages and dendritic cells . Commer US 2018 /0112180 A1 Apr. 26 , 2018

cial sources of poly ( I : C ) for use with the invention include, for use in modulating cells according to the invention , but are not limited to , InvivogenTM (CAS number 31852 include, but are not limited to PGE2, dmPGE2, 15 ( S ) - 15 29 - 6 ) ; TocrisTM (CAS number 24939 - 03 - 5 ) , GE Healthcare methyl PGE2 , 20 - ethyl PGE2, 8 - iso - 16 - cyclohexyl- tetranor Life SciencesTM ( Product Code 27 - 4732 -01 ) , and Sigma PGE2, and PGE , analogues . In certain embodiments , AldrichTM (CAS Number 42424 - 50 - 0 ) . PGE R2 and PGE R4 agonists and analogues thereof are of [ 0135 ] In some aspects of the invention , cells are modu particular interest, and in some embodiments , the agent lated with one ormore polynucleotides capable of increasing preferentially binds and activates a PGE , EP2 or PGE , EP4 PD - L1 and / or IDO - 1 expression . Suitable polynucleotides receptor . include exogenous polynucleotides that encode one or more [0141 ] As used herein , the terms “ prostaglandin E , " or functional PD -L1 polypeptides. Suitable polynucleotides “ PGE ” include, without limitation , any naturally - occurring may include exogenous polynucleotides that encode one or or chemically synthesized PGE , molecule , as well as “ ana more functional IDO - 1 polypeptides. Such polynucleotides logues” thereof. As used herein , the term “ analogue” or may form part of an expression cassette which is used to relates to a chemical molecule that is similar to another genetically modify the cell to express an exogenous PD -L1 chemical substance , e .g ., PGE2, in structure and function , or IDO - 1 polypeptide. Polynucleotides for use with the often differing structurally by a single element or group , but invention include , but are not limited to , those that encode may differ by modification of more than one group ( e .g . , 2 , human , mouse , rabbit, rat, bovine, horse , goat or non -human 3 , or 4 groups ) if it retains the same function as the parental primate PD -L1 or IDO - 1 polypeptides. chemical. [0136 ] In one embodiment , the expression cassette is (0142 ] Illustrative examples of PGE , " analogues” include , included in a vector. Thus , in one aspect , the cells are without limitation , 16 , 16 - dimethyl PGE2 (“ dmPGE2 " ) , modulated with a vector comprising one or more polynucle p - ( p - acetamidobenzamido ) phenyl ester, 11 -deoxy - 16 , otides capable of increasing PD -L1 and/ or IDO - 1 expres 16 -dimethyl PGE2, 9 -deoxy - 9 -methylene - 16 , 16 - dimethyl sion . Examples of vectors used for such purposes include PGE2, 9 -deoxy - 9 -methylene PGE2, 9 -keto Fluprostenol, expression plasmids capable of directing the expression of 5 - trans PGE , 17 - phenyl- omega -trinor PGE , PGE , serinol the nucleic acids in the target cell. In other instances , the amide, PGE , methyl ester , 16 -phenyl tetranor PGE2 , 15 ( S ) vector is a viral vector system wherein the nucleic acids are 15 -methyl PGE2 , 15 ( R ) - 15 -methyl PGE2, 8 - iso - 15 -keto incorporated into a viral genome that is capable of trans PGE, , 8 - iso PGE , isopropyl ester, 8 - iso - 16 - cyclohexyl- tet fecting the target cell. In a preferred embodiment, the ranor PGE2, 20 -hydroxy PGE2, 20 - ethyl PGE2, 11 -deoxy polynucleotides can be operably linked to expression and PGE1, nocloprost , sulprostone , butaprost , 15 -keto PGE2, control sequences that can direct expression of the gene in and 19 ( R ) hydroxy PGE2. Also included are prostaglandin the desired target host cells. Thus , one can achieve expres analogues having a similar structure to PGE2 that are sub sion of the nucleic acid under appropriate conditions in the stituted with halogen at the 9 -position ( see , e . g . , WO target cell. 2001112596 , herein incorporated by reference in its [ 0137 ] Viral vector systems useful in the expression of the entirety ) , as well as 2 - decarboxy - 2 - phosphinico prostaglan present nucleic acids include, for example , naturally occur din derivatives , such as those described in U . S . Publication ring or recombinant viral vector systems. Depending upon No . 2006 /0247214 , herein incorporated by reference in its the particular application , suitable viral vectors include entirety ) . replication competent, replication deficient, and condition [ 0143 ] PGE , analogues , including without limitation ally replicating viral vectors . For example , viral vectors can alprostadil , can also be used to activate the PGE , R , ( EP ) be derived from the genome of human or bovine adenovi and PGE2R4 (EP _ ) cell signaling pathways, and are contem ruruses , vaccinia virus, herpes virus, adeno - associated virus, plated as agents useful in the methods of the invention . minute virus of mice (MVM ), HIV , sindbis virus, and [0144 ] Without being limited to any particular theory or retroviruses ( including but not limited to Rous sarcoma mechanism , stimulation / activation of the PGE , R , ( EP ) and virus ), Sendai Virus, and MOMLV. Typically , the genes of PGE R4 (EP _ ) cell signaling pathways result in an increase interest are inserted into such vectors to allow packaging of in expression of PD -L1 and / or IDO - 1 . Accordingly , in one the gene construct, typically with accompanying viral DNA , embodiment, a “ non - PGE2- based ligand ” that binds to and followed by infection of a sensitive host cell and expression stimulates PGE R2 and PGE2R4 receptors ( i. e ., a PGE , R ! of the gene of interest. Accordingly , in one embodiment, the PGE , R4 agonist ) is contemplated for use in the methods of cells to be modulated are contacted with a viral vector the invention . Illustrative examples of non - PGE2- based EP2 comprising one or more polynucleotides capable of increas receptor agonists include CAY10399 , ONOO _ 8815Ly , ing PD -L1 and /or IDO - 1 expression . ONO - AE1- 259 , CP -533 , 536 and carbazoles and fluorenes [0138 ] ii. Prostaglandin Pathway Agonists disclosed in WO 2007 /071456 . [0139 ] In some aspects of the invention , cells are modu [0145 ] Illustrative examples of non -PGE -based EP4 ago lated to increase PD -L1 and / or IDO - 1 expression by contact nists include ONO -4819 , APS - 999 Na, AH23848 , ONO with one or more prostaglandin pathway agonists. Such AE1- 329 , and other non - PGE , -based EP , agonists disclosed prostaglandin pathway agonists include , but are not limited in WO / 2000 /038663 ; U . S . Pat . No. 6 , 747 ,037 ; and U . S . Pat . to , cAMP analogues or enhancers , Ga -s activators , com No . 6 ,610 ,719 ) . pounds that selectively bind the PGE , EP2 or the PGE , EP4 [0146 ] In some aspects of the invention , cells are modu receptor , glucocorticoids, and combinations thereof. lated with agents that are selective for , and preferentially [0140 ] As used herein , the term “ prostaglandin pathway bind to , PGE , EP4 receptors. Such agents have a higher agonist” refers to an agent that stimulates prostaglandin cell affinity for the EPA receptor than for any of the other three signaling pathways, including an agent that stimulates the EP receptors namely EP1, EP2 and EP 3 . Agents that selec PGE , R , and / or PGE , R4 cell signaling pathways . Illustrative tively bind the PGE EP , receptor include , but are not limited examples of prostaglandin pathway agonists that are suitable to , agents selected from the group consisting of: 5 - [ ( 1E , 3R ) US 2018 /0112180 A1 Apr. 26 , 2018

4 , 4 -difluoro - 3 -hydroxy - 4 - phenyl- 1 -buten - 1 - yl) - 1- [6 - ( 2H - tet nazine ) , and various others such as isometheptene mucate , razol -5R -yl ) hexyl] - 2 -pyrrolidinone ; 2 - [ 3 - [ ( 1R ,2S , 3R ) - 3 -hy dihydrostreptomycin sulfate , protriptyline, telenzepine , droxy - 2 - [ ( E ,3S ) - 3 -hydroxy - 5 - [ 2 - methoxymethyl) phenyl] cyclobenzaprine , and 4 -aminosalicylic acid . pent- 1 - enyl] - 5 -oxocyclopentyljsulfanylpropylsulfanyl ] [0154 ] B . Cells acetic acid ; methyl 4 - [ 2 - [ ( 1R 2R 3R ) - 3 -hydroxy - 2 - [ ( E , 3S ) 3 -hydroxy - 4 - [ 3 - methoxymethyl )phenyl ] but - 1 -enyl ] - 5 -oxo [0155 ] Aspects of the invention relate to the cells which cyclopentyl] ethylsulfanyl] butanoate ; 16 - ( 3 -Methoxym are modulated to achieve increased PD -L1 and/ or IDO - 1 ethyl) phenyl - ro - tetranor- 5 - thiaPGE ; 5 - { 3 - [ ( 2S ) - 2 - { ( 3R ) - 3 expression . Accordingly , the invention may be practiced hydroxy -4 - [ 3 - ( trifluoromethyl) phenyl ] butyl ) - 5 with any cell or combination of cells that responds to oxopyrrolidin - 1 -yl ) propyl ] thiophene - 2 -carboxylate ; [4 '- [ 3 modulation with one or more agents capable of increasing butyl- 5 - oxo - 1 -( 2 -trifluoromethyl - phenyl ) - 1, 5 -dihydro -[ 1 ,2 , PD - L1 expression in the cell or combination of cells. 4 ]triazol -4 -ylmethyl ]- biphenyl - 2 - sulfonicacid ( 3 -methyl [0156 ] Cells for use with the invention may be autologous , thiophene - 2 -carbonyl ) - amide ] ; and ( Z ) - 7 - { ( 1R ,4S , 5R ) -5 allogeneic , syngeneic or xenogeneic with respect to the [ ( E ) - 5 - ( 3 - chloro - benzo [ b ]thiophene - 2 - yl) - 3 - hydroxy - pent subject to which they are administered . “ Autologous, ” as 1 - enyl] - 4 - hydroxy - 3 , 3 -dimethyl - 2 - oxo -cyclopentyl } -hept used herein , refers to cells from the same subject. “ Alloge 5 -enoic acid ) , and pharmaceutically acceptable salts of any neic , ” as used herein , refers to cells of the same species that of these agents . differ genetically to the cell in comparison . “ Syngeneic , ” as [0147 ] In particular embodiments , the prostaglandin path used herein , refers to cells of a different subject that are way agonist comprises PGE2, 16 , 16 - dmPGE2, 15 ( S ) - 15 genetically identical to the cell in comparison . “ Xenoge methyl PGE2, 20 - ethyl PG E2, or 8 - iso - 16 - cyclohexyl- tet neic , ” as used herein , refers to cells of a different species to ranor PGE2. the cell in comparison . In preferred embodiments , the cells [0148 ] iii. Glucocorticoids of the invention are allogeneic . [ 0149 ] In some aspects of the invention , cells are modu [0157 ] Cells for use with the invention include , but are not lated for increased PD -L1 and /or IDO - 1 expression by limited to stem cells , progenitor cells, and differentiated contact with glucocorticoids and / or glucocorticoid receptor cells . The stem cells described herein may comprise embry agonists. onic stem cells , induced pluripotent stem cells, bone marrow [ 0150 ] Illustrative examples of glucocorticoids and gluco stem cells , umbilical cord stem cells , placental stem cells , corticoid receptor agonists suitable for use with the inven mesenchymal stem cells , neural stem cells , liver stem cells , tion include, but are not limited to , medrysone , alclometa pancreatic stem cells , cardiac stem cells , T cells , kidney stem sone , alclometasone dipropionate , amcinonide , cells , hematopoietic stem cells and muscle stem cells . The beclometasone, beclomethasone dipropionate , betametha cells may be obtained from a tissue explant, a primary sone , betamethasone benzoate , betamethasone valerate , culture of cells , clonal cells , or serially expanded cells . budesonide , ciclesonide, clobetasol, clobetasolbutyrate , clo [0158 ] The cells may be present in a cell population . Cell betasol propionate , clobetasone , clocortolone , cloprednol, populations include whole blood samples , e .g . , whole cord cortisol, cortisone , cortivazol, deflazacort, desonide , desoxi blood , whole mobilized peripheral blood , whole bone mar metasone, desoxycortone, desoxymethasone, dexametha row samples ; isolated cells expressing particular markers , sone , diflorasone , diflorasone diacetate , diflucortolone , dif e . g . , CD34 + ; and hematopoietic stem and progenitor cells . lucortolone valerate , difluorocortolone , difluprednate , Suitable sources of cells for use in the methods of the present fluclorolone , fluclorolone acetonide, fludroxycortide, flu invention include , but are not limited to , cells isolated or metasone , flumethasone , flumethasone pivalate , flunisolide , obtained from an organ or tissue of thebody containing cells flunisolide hemihydrate , fluocinolone, fluocinolone ofhematopoietic origin . By “ isolated ” is meant material that acetonide, fluocinonide , fluocortin , fluocoritin butyl, fluo is removed from its original environment . For example , a cortolone , fluorocortisone , fluorometholone , fluperolone, cell is isolated if it is separated from some or all of the fluprednidene , fluprednidene acetate , fluprednisolone , fluti components that normally accompany it in its native state . casone , fluticasone propionate , formocortal, halcinonide , For example , an “ isolated population of cells, ” an “ isolated halometasone, hydrocortisone, hydrocortisone acetate , source of cells , " or " isolated hematopoietic stem cells ” and hydrocortisone aceponate , hydrocortisone buteprate , hydro the like , as used herein , refer to in vitro or ex vivo separation cortisone butyrate , loteprednol, meprednisone , 6a -methyl of one or more cells from their natural cellular environment, prednisolone , methylprednisolone , methylprednisolone and from association with other components of the tissue or acetate , methylprednisolone aceponate , mometasone , organ , e . g ., it is not significantly associated with in vivo mometasone furoate , mometasone furoate monohydrate , substances . paramethasone , prednicarbate , prednisolone , prednisone , [0159 ] Populations of cells described herein can be prednylidene , rimexolone, tixocortol, triamcinolone , triam obtained from bone marrow , umbilical cord blood , mobi cinolone acetonide and ulobetasol, as well as combinations lized peripheralblood , Wharton ' s jelly , placenta , fetal blood , thereof. or obtained from an induced pluripotent stem cell ( iPSC ) . [0151 ] In particular embodiments , the glucocorticoid [ 0160 ] In one embodiment, the present compositions and comprises betamethasone , clobetasol proprionate , flumetha methods may use a “ hematopoietic cell ,” e . g ., a cell selected sone , flucinolone acetonide ,medrysone , hydrocortisone , tri from the continuum of cells ranging from a HSPC , to a fully amcinolone , alclometasone , or dexamethasone . In more differentiated blood cell, including all the cells of the particular embodiments , the glucocorticoid is medrysone. myeloid and lymphoid lineages. Thus , in one embodiment, [0152 ] iv . Other Agents a suitable source of cells for use in the methods of the [ 0153] Other agents of particular interest with IDO - 1 present invention includes, but is not limited to , cells iso include antineoplastics ( such as gemcitabine , letrozole , and lated or obtained from an organ or tissue of the body fludarabine) , dopamine receptor antagonists ( e . g . , flupher containing cells of hematopoietic origin . In another embodi US 2018 /0112180 A1 Apr. 26 , 2018 ment, the cell may be obtained from an iPSC or a population cells ( iPSCs ) and embryonic stem cells (ESCs ) ) . As used of iPSCs, where the iPSC ( s ) are differentiated to form a herein , the term “ induced pluripotent stem cell” or “ iPSC ” hematopoietic cell . refers to a non -pluripotent cell that has been reprogrammed [0161 ] Thus, hematopoietic cells for modulation and use to a pluripotent state . Once the cells of a subject have been in the methods described herein can be obtained from bone reprogrammed to a pluripotent state, the cells can then be marrow . Hematopoietic cells for modulation and use in the differentiated to a desired cell type , such as a hematopoietic methods described herein can be obtained from umbilical stem or progenitor cell . As used herein , the terms “ repro cord blood . Hematopoietic cells for modulation and use in gramming ” refers to a method of increasing the potency of the methods described herein can be obtained from mobi- a cell to a less differentiated state . Suitable methods and lized peripheral blood . Hematopoietic cells for modulation materials for reprogramming a cell ( e . g . somatic cell ) to an and use in the methods described herein can be obtained iPSC include , but are not limited to , those disclosed in the from Wharton ' s jelly . Hematopoietic cells for use in the following documents , the entire contents of which are incor methods described herein can be obtained from placenta . porated by reference : U . S . Patent Publication No . 2011/ Hematopoietic cells for modulation and use in the methods 0076678 , U . S . Patent Publication No . 2013/ 0102074 , U . S . described herein can be obtained from fetal blood . Patent Publication No. 2010 /0310525 , U . S . Patent Publica [0162 ] Hematopoietic cells described herein can be tion No . 2011 /0110899 , U . S . Patent Publication No . 2007 / obtained or isolated from unfractionated or fractioned bone 0254884 , US 2012 / 0028351, U . S . Patent Publication No . marrow of adults , which includes femurs , hip ( e. g . iliac 2012 /0264218 , U . S . Pat. No. 8 , 932 , 856 , Yamanaka et al . crest ), ribs , sternum , or any other bone containing marrow . Cell. 2006 Aug . 25 ; 126 ( 4 ) :663 - 76 , Zhou et al. Cell Stem Hematopoietic cells described herein can be obtained or Cell Stem Cell . 2009 May 8 ; 4 ( 5 ) : 381 - 4 ; Wemig et al. isolated directly by removal from the hip using a needle and Nature . 2007 Jul. 19 ; 448 ( 7151) : 318 - 24 ; Okita et al. Sci syringe , or from the blood , often following pre - treatment ence . 2008 Nov . 7 ; 322 (5903 ): 949 - 53 ; Woltjen et al. Nature . with cytokines , such as G -CSF ( granulocyte colony - stimu 2009 Apr. 9 ; 458 ( 7239 ) : 766 - 70 , U . S . Patent Publication No . lating factors ) , that induce cells to be released or mobilized 2010 /0233804 ; U . S . Patent Publication No . 2012 /0264218 ; from the bone marrow compartment. Other sources of U . S . Pat . No . 7 ,592 , 177 ; U . S . Pat. No . 7 , 951, 592 ; U . S . Pat . hematopoietic cells described herein include umbilical cord No . 8 ,071 , 369; U . S . Pat . No. 8 ,309 , 555 ; and U . S . Pat . No . blood , placental blood , and mobilized peripheral blood . 8 , 906 ,677 . [0163 ] The hematopoietic cells described herein can be [0166 ] Hematopoietic cells described herein can be puri harvested ( e . g . , isolated ) from a hematopoietic source , e . g ., fied using techniques well known in the art. For example , the bone marrow cells , umbilical cord blood , or mobilized human hematopoietic cells (for instance HSPCs) described peripheral blood cells . “ Harvesting ” hematopoietic stem and herein can be purified using FACS or flow cytometry as progenitor cells is defined as the dislodging or separation of understood in the art and exemplified in , for example , U . S . cells from the matrix . This can be accomplished using a Ser. No. 13 /257 , 290 ( US 20120202288 ) , which is herein number ofmethods known in the art including , for example , incorporated in full by reference . HSPCs for use with the enzymatic , non - enzymatic , centrifugal, electrical, or size invention may also be derived from a clonal cell line . based methods , or preferably , by flushing the cells using [0167 ] Hematopoietic cells described herein , whether media ( e . g . , media in which the cells are incubated ) . In obtained from cord blood , bonemarrow , peripheral blood , or particular embodiments , harvesting a sufficient quantity of other source , can be grown , treated or expanded in any cells for transplantation can be obtained by mobilizing the suitable , commercially available or custom defined medium , stem and progenitor cells in the donor. with or without serum , as desired ( see , e . g . , Hartshorn et al. , [0164 ] In some aspects of the invention , HPSCs are Cell Technology for Cell Products , pages 221 - 224 , R . Smith , obtained from mobilized peripheral blood . “ Hematopoietic Editor; Springer Netherlands, 2007 , herein incorporated by stem cell mobilization ” refers to the release of stem cells reference in its entirety ) . For instance , in certain embodi from the bone marrow into the peripheral blood circulation ments , serum free medium can utilize albumin and /or trans for the purpose of leukapheresis , prior to transplantation . ferrin , which can be useful for the growth and expansion of, Hematopoietic growth factors , e . g ., granulocyte colony for example , CD34 + cells in serum free medium . Cytokines stimulating factor (G -CSF ) or chemotherapeutic agents can be included , such as, but not limited to , Flt - 3 ligand , often are used to stimulate the mobilization . Commercial stem cell factor ( SCF ) , thrombopoietin ( TPO ) , and IL - 6 , stem cell mobilization drugs, e. g. , MOZOBILTM , can be among others . Hematopoietic cells ( for instance HSPCs ) can used in combination with G -CSF to mobilize sufficient be grown in vessels such as bioreactors ( see , e . g . , Liu et al. , quantities of HPSCs for transplantation into a subject. Mobi Journal of Biotechnology 124 :592 - 601 , 2006 , herein incor lized peripheral blood may be obtained by treating a donor p orated by reference in its entirety ) . A suitable medium for with an agent that promotes recruitment of hematopoietic ex - vivo expansion of HSPCs can include HSPC supporting stem /progenitor cells (HPSC ) from the bone marrow into cells, such as stromal cells ( e . g ., lymphoreticular stromal peripheral blood . Suitable agents and methods for mobiliz cells ) . Stromal cells can be derived , for instance , from the ing peripheral blood for use in the invention include, but are disaggregation of lymphoid tissue . Stromal cells can support not limited to , those disclosed in the following references, the in vitro , ex vivo , and in vivo maintenance , growth , and the disclosure of which are incorporated by reference in their differentiation of HSPCs, as well as their progeny . entirety : Lemoli et al. , Haematologica , 2008 March : 93 : 321 [0168 ] When transplanted into irradiated humans , 324 ; Pelus , Curr Opin Hematol. 2008 July ; 15 (4 ) : 285 - 92 ; hematopoietic cells described herein ( e . g ., modulated and US 2012 /0003189 . hematopoietic cells ) can repopulate the erythroid , neutro [0165 ] Hematopoietic cells for use in the therapeutic com phil- macrophage , megakaryocyte , and lymphoid positions and methods of the invention can be obtained from hematopoietic cell pool. HSPCs described herein can be pluripotent stem cell sources ( e . g . , induced pluripotent stem identified according to certain phenotypic or genotypic US 2018 /0112180 A1 Apr. 26 , 2018 markers . For example , HSPCs can be identified by their [0172 ] Other low or medium resolution methods to deter small size , lack of lineage ( lin ) markers , low staining (side mine HLA type examine the HLA isoforms of the individual , population ) with vital dyes such as rhodamine 123 (rhod but do not rely on determining the actual sequence of an amineDULL , also called rhoo) or Hoechst 33342 , and by the individual' s HLA alleles . Often , the donor is related to the presence of various antigenic markers on their surface ,many individual receiving the sample and in such instances , sero of which belong to the cluster of differentiation series ( e . g ., typing alone or in combination with other low or medium CD34 , CD38 , CD90 , CD133 , CD105 , and c -kit , the receptor resolution methods can be sufficient to determine if a sample for stem cell factor ) . In some aspects , HSPCs are CD34 + is suitable for administration . In instances where a donor is cells . HSPCs described herein can be considered negative not related to the recipient, HLA type can be a five out of six for the markers that are typically used to detect lineage or lower match . In such instances it can be useful to use cells commitment, and , thus , are often referred to as Lin ( - ) cells . or tissues with a lower match rather than expend time and Most human HSPCs ( e. g . hHSPCs) can be characterized as effort to find a better HLA type match . CD34 + , CD59 + , Thy1 /CD90 + , CD38101 - , C -kit /CD117 + , [0173 ] High resolution methods involve examining the and Lin ( - ) . However, not all stem cells are covered by these specific sequence of the HLA genes or gene expression combinations, as certain HSPCs are CD34 - ICD38 – . Also products (protein or RNA ) . High resolution methods can some studies suggest that earliest stem cells can lack c - kit on distinguish between thousands of different isoforms. HLA the cell surface . For HSPCs, CD133 can represent an early typing of the HSPCs and enhanced -HSPCs can be per marker. CD34 + and CD34 -HSPCs in certain instances have formed for six HLA loci, HLA - A , - B , and -DR , for example , been shown to be CD133 + . CD34 + and Lin ( - ) cells can also at low resolution /split antigen level. include hematopoietic progenitor cells . 10174 ] DNA -based testing methods can be utilized for [0169 ] The cells described herein can be HLA typed and HLA -DR typing . DNA - based testing can be used for can be matched or partially matched to a specific subject for HLA - A and - B . Transplant center guidelines for typing of the administration . Alternatively , the cells may be subject, family and to confirm the HLA types of potential unmatched to a specific subject for administration . HLA unrelated donors include , typing HLA - A , B , and - DR loci type refers to the unique set of proteins called human using primarily DNA - based testing methods at allele level leukocyte antigens . These proteins are present on each resolution for DRBI and low resolution / split antigen level individual' s cells and allow the immune system to recognize for HLA - A and - B . The typing of a subject and the selected ‘ self from ` foreign ' . Administration of cells or tissues that donor can be performed using the same set of reagents , are recognized as foreign can lead to compatibility problems methodology , and interpretation criteria with fresh tissue including , for example , immunorejection or graft versus host samples to ensure HLA identity . Quality assurance and disease (GVHD ) . There are six major HLAS (HLA - A , quality control for HLA testing are complied with . HLA - B , HLA - C , HLA -DR , HLADP, and HLA -DQ ) . Each [0175 ] Accordingly, compositions used in the methods HLA antigen has multiple isoforms in the human population , described herein can include haplotyped enhanced -HSPCs . and each individual can have two different isoforms for each The enhanced -HSPCs can be HLA typed based on H LA - A , HLA due to the diploid nature of our genome. Therefore , a HLA - B , HLA - C , and HLA -DRB1 . The enhanced -HSPCs complete match would match twelve out of twelve isoforms. can be HLA typed based on a matched HLA group with a A cell or tissue donated from the same individual as, or an specific human subject . The HLA haplotyped enhanced identical twin of, the intended recipient would have a perfect HSPCs can include 6 out of 6 HLA matches with a specific HLA -type and is referred to as syngeneic or autologous . It human subject . The HLA haplotyped enhanced - HSPCs can include 5 out of 6 HLA matches with a specific human is also understood that certain factors including but not subject. The HLA haplotyped enhanced - HSPCs can include limited to ethnic background and race correlate with certain 4 out of 6 HLA matches with a specific human subject. HLA HLA - types. matching can be based on alleles or antigens , and combi [0170 ] Many major and minor HLA isoforms exist and it nations thereof. is understood that a suitable match can include a match [0176 ] Percentages of Cells by Type in Population of Cells between a subset of the major HLAs, all the major HLAS, [0177 ] The methods and compositions described herein some or all major and minor HLAs or any combination can include a plurality of cells ( e . g . , a cell population ) that known to the art thatmitigates immuno - rejection or GVHD . is about 0 . 1 % to about 1 % , about 1 % to about 3 % , about 3 % It is also understood that specific guidelines for what con to about 5 % , about 10 % to about 15 % , about 15 % - 20 % , stitutes a good HLA - type match depends on many factors . about 20 % - 25 % , about 25 % -30 % , about 30 % -35 % , about Therefore, judgment must be made by one skilled in the art 35 % - 40 % , about 40 % - 45 % , about 45 % - 50 % , about 60 % to assess the suitability of a given cell or tissue sample for 70 % , about 70 % - 80 % , about 80 % - 90 % , about 90 % - 95 % , or transplant into a given individual . about 95 % to about 100 % HSPCs. The population of cells [0171 ] HLA type can be determined using methods known can be about 0 . 1 % to about 1 % HSPCs . The population of in the art, including for example low resolution methods, cells can be about 1 % to about 3 % HSPCs. The population such as by sero - typing, or using antibody based methods . of cells can be about 3 % to about 5 % HSPCs. The popula Sero -typing is based on antibody recognition of HLA types . tion of cells can be about 10 % to about 15 % HSPCs. The Sero -typing can distinguish between 28 different HLA - A population of cells can be about 15 % - 20 % HSPCs. The genes, 59 HLA - B genes and 21 HLA -C genes. A perfect population of cells can be about 20 % -25 % HSPCs. The match by sero - typing methods would be a six out of six population of cells can be about 25 % -30 % HSPCs. The match referring to the two alleles for each HLA ( A , B , and population of cells can be about 30 % - 35 % HSPCs . The C ) present in each individual. In certain instances, a five out population of cells can be about 35 % -40 % HSPCs. The of six match or less can be considered a good match as population of cells can be about 40 % -45 % HSPCs . The determined by one skilled in the art . population of cells can be about 45 % - 50 % HSPCs . The US 2018 /0112180 A1 Apr. 26 , 2018 population of cells can be about 60 % -70 % HSPCs. The [0181 ] In one embodiment, the hematopoietic cells may be population of cells can be about 70 % - 80 % HSPCs. The enriched or purified by depletion of other cell types, or population of cells can be about 80 % - 90 % HSPCs. The purification for a desired cell marker. Hematopoietic cells population of cells can be about 90 % - 95 % HSPCs. The described herein for use in the methods described herein can population of cells can be about 95 % to about 100 % HSPCs. be depleted of mature hematopoietic cells such as T cells , B [0178 ] The methods and compositions described herein cells , NK cells , dendritic cells , monocytes , granulocytes , can include a plurality of hematopoietic cells ( e . g . , a cell erythroid cells , and their committed precursors from bone population ) that is about 1 % , 5 % , 10 % , 20 % , 30 % , 40 % . marrow aspirate , umbilical cord blood , or mobilized periph 50 % , 60 % , 70 % , 80 % , 85 % , 90 % , 95 % , 96 % , 97 % , 98 % , eral blood (mobilized leukapheresis product ) . Mature , lin 99 % , or 100 % HSPCs. The population of cells can be about eage committed cells can be depleted by immunodepletion 1 % HSPCs . The population of cells can be about 5 % HSPCs . using methods known in the art. For example , immu The population of cells can be about 10 % HSPCs . The nodepletion can be performed by labeling solid substrates population of cells can be about 20 % HSPCs . The popula with antibodies that bind to a panel of lineage antigens : (e . g ., tion of cells can be about 30 % HSPCs . The population of CD2, CD3, CD11b , CD14 , CD15 , CD16 , CD19 , CD56 , cells can be about 40 % HSPCs. The population of cells can CD123 , or CD235a ) . A subsequent step can be performed to be about 50 % HSPCs. The population of cells can be about further purify the population of cells . The subsequent step 60 % HSPCs. The population of cells can be about 70 % includes a substrate labeled with antibodies that binds to the HSPCs. The population of cells can be about 80 % HSPCs. CD34 + antigen . Such techniques can be used to isolate The population of cells can be about 85 % HSPCs. The primitive hematopoietic stem and progenitor cells . Kits are population of cells can be about 90 % HSPCs. The popula commercially available for purifying hematopoietic stem tion of cells can be about 95 % HSPCs. The population of and progenitor cells from various cell sources and in par cells can be about 96 % HSPCs. The population of cells can ticular embodiments , these kits are suitable for use with the be about 97 % HSPCs. The population of cells can be about methods of the present invention . Exemplary commercially 98 % HSPCs. The population of cells can be about 99 % available kits for purifying hematopoietic stem and progeni HSPCs. The population of cells can be about 100 % HSPCs. tor cells include , but are not limited to Lineage (Lin ) [0179 ] The populations of cells described above can Depletion Kit (Miltenyi Biotec ); CD34 + enrichment kit include about 0 . 1 % to about 1 % , about 1 % to about 3 % , (Miltenyi Biotec ) ; RosettaSep (Stem Cell Technologies ) . about 3 % to about 5 % , about 10 % -about 15 % , about 15 % [0182 ] The plurality of hematopoietic cells ( e . g . , “ cell 20 % , about 20 % - 25 % , about 25 % - 30 % , about 30 % -35 % , population " or " population " ) can include less than about about 35 % -40 % , about 40 % -45 % , about 45 % - 50 % , about 30 % , 25 % , 20 % , 15 % , 10 % or 5 % mesenchymal stem cells . 60 % - 70 % , about 70 % - 80 % , about 80 % - 90 % , about 90 % The plurality of hematopoietic cells can include no more 95 % , or about 95 % to about 100 % CD34 + cells . The than about 10 % mesenchymal stem cells. Mesenchymal populations of cells described above can include about 1 % stem cells (MSCs ) are multipotent stem cells that can CD34 + cells . The populations of cells described above can differentiate readily into lineages including osteoblasts , include about 3 % CD34 + cells . The populations of cells myocytes , chondrocytes , and adipocytes ( Pittenger, et al. , described above can include about 5 % CD34 + cells . The Science , Vol. 284 , pg . 143 ( 1999 ) ; Haynesworth , et al. , populations of cells described above can include about 10 % Bone, Vol. 13 , pg. 69 ( 1992 ) ; Prockop , Science , Vol. 276 , pg . CD34 + cells . The populations of cells described above can 71 ( 1997) ). include about 20 % CD34 + cells . The populations of cells [0183 ] The plurality of hematopoietic cells can include described above can include about 30 % CD34 + cells . The less than about 30 % , 25 % , 20 % , 15 % , 10 % or 5 % endothe populations of cells described above can include about 40 % lial progenitor cells . The plurality of hematopoietic cells can CD34 + cells. The populations of cells described above can include less than about 10 % endothelial progenitor cells . As include about 50 % CD34 + cells . The populations of cells used herein , the term " endothelial progenitor cell” refers to described above can include about 60 % CD34 + cells . The a multi potent or unipotent cell with the potential to differ populations of cells described above can include about 70 % entiate into vascular endothelial cells . The plurality of CD34 + cells . The populations of cells described above can hematopoietic cells can include no more than about 10 % include about 80 % CD34 + cells . The populations of cells mesenchymal stem cells or endothelial progenitor cells . described above can include about 85 % CD34 + cells. The [0184 ] The plurality of hematopoietic cells as obtained populations of cells described above can include about 90 % from a donor ( e . g . , isolated from a donor ), or as otherwise CD34 + cells . The populations of cells described above can provided , can be substantially free of mesenchymal stem include about 95 % CD34 + cells . The populations of cells cells and / or endothelial progenitor cells ( e . g . , less than about described above can include about 96 % CD34 + cells . The 10 % mesenchymal stem cells and less than about 10 % populations of cells described above can include about 97 % endothelial progenitor cells ) . The plurality of hematopoietic CD34 + cells . The populations of cells described above can cells can alternatively be depleted of mesenchymal stem include about 98 % CD34 + cells . The populations of cells cells and / or endothelial progenitor cells using methods described above can include about 99 % CD34 + cells . The known in the art, for example, using immunomagnetic populations of cells described above can include about selection techniques , fluorescence activated cell sorting , or a 100 % CD34 + cells . combination therein . The depletion methods can further [0180 ] Cells can undergo a number ofmanipulations prior include using at least one antibody specific for at least one to being modulated . For example , cells can be purified , of the cell - surface markers described herein . expanded , split, cryopreserved , or enzymatically digested , [0185 ] The plurality of hematopoietic cells can be prior to or after modulation with one or more agents to depleted of endothelial progenitor cells , including endothe increase therapeutic potential and / or expand the cell popu lial progenitor cells positive for the CD14 cell surface lation . marker and negative for CD45 (CD14 + /CD45 - ) and /or cells US 2018 /0112180 A1 Apr. 26 , 2018 13 positive for VWF ( Von Willebrand Factor ) (VWF + ). The described herein , and subsequently cryopreserved for a plurality of HSPCs can be depleted of cells positive for period of time prior to administration to a subject. Cryo CD73 and / or CD140B cell surface markers (CD73 + / preservation of the modulated hematopoietic cells may CD140B + ) . The plurality of hematopoietic cells can include occur within 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , or 24 hours cells positive for the cell surface marker CD34 , and include of treatment of the cells using themethods described herein , less than about 30 % , 25 % , 20 % , 15 % , 10 % or 5 % of cells as well as any time intervening these specific time points . positive for a cell surface marker selected from the group [0189 ] Hematopoietic cells may or may not be cultured consisting of CD73 , CD140B , CD14 and VWF. prior to ex vivo contact with an exogenous agent ( e. g ., a [ 018 ] The plurality of hematopoietic cells can include glucocorticoid ) as described herein . In aspects where the CD34 + cells and include less than about 30 % , 25 % , 20 % , hematopoietic cells are cultured prior to ex vivo contact with 15 % , 10 % or 5 % CD14 + /CD45 - cells . The plurality of an exogenous agent, the hematopoietic cells may be cultured hematopoietic cells can include CD34 + cells and include less than about 24 hours , less than about 12 hours , less than less than about 30 % , 25 % , 20 % , 15 % , 10 % or 5 % VWF + about 10 hours , less than about 8 hours, less than about 6 cells . The plurality of HSPCs can include CD34 + cells and hours , less than about 4 hours , or less than about two hours . include less than about 30 % , 25 % , 20 % , 15 % , 10 % or 5 % Hematopoietic cells may or may not be cultured prior to CD140B + cells . administration to a subject. Where the hematopoietic cells [0187 ] The plurality of human hematopoietic cells can are cultured prior to administration to a subject, the include CD34 + hematopoietic cells and include less than hematopoietic cells can be cultured for less than about 24 about 30 % , 25 % , 20 % , 15 % , 10 % or 5 % of CD 14 + /CD45 hours, or less than about 12 hours , less than about 10 hours , cells , VWF + cells , CD73 + cells , and CD140B + cells . The less than about 8 hours , less than about 6 hours , less than plurality of human hematopoietic cells can be positive for about 4 hours , or less than about two hours . The hematopoi the cell surface marker CD34 and negative for at least one etic cells can be cultured for about 2 hours . The hematopoi cell surface marker from the group consisting of CD14 , etic cells can be cultured for less than about 24 hours . The VWF, CD73 , and CD140B . The plurality of human hematopoietic cells can be cultured for less than about 12 hematopoietic cells can be positive for the cell surface hours , 10 hours , 8 hours , 6 hours , 4 hours , or two hours . The marker CD34 and negative for the cell surface markers hematopoietic cells can be cultured for about 2 hours . CD14 , VWF, CD73 , and CD140B . [0190 ] The hematopoietic cells may or may not be [0188 ] The hematopoietic cells described herein may or expanded prior to contact of the hematopoietic cells with may not be expanded or split prior to administration . The exogenous agents to obtain modulated hematopoietic cells hematopoietic cells may or may not be expanded ex vivo or as described herein . Hematopoietic cells , whether obtained in vitro prior to administration to a subject. An unexpanded from cord blood , bone marrow , peripheral blood , Wharton ' s plurality of modulated hematopoietic cells can be obtained jelly , placental blood or other source , can be grown or and administered to a subject, where the plurality of modu expanded in any suitable , commercially available or custom lated hematopoietic cells are derived using the methods defined medium , with or without serum , as desired ( see , e . g . , described herein ( e . g . , treating hematopoietic cells ex vivo Hartshorn et al. , Cell Technology for Cell Products , pages as described herein ). The methods to generate a plurality of 221 - 224 , R . Smith , Editor ; Springer Netherlands , 2007 , modulated hematopoietic cells can further include a washing herein incorporated by reference in its entirety ) . For step to remove the exogenous agent prior to administration . instance , serum free medium can utilize albumin and / or The cells can be obtained from a donor ( e . g . , via cord blood ) transferrin , which have been shown to be useful for the and not expanded prior to or after ex vivo treatment of the growth and expansion of CD34 + cells in serum free cells as described herein , or at any time prior to adminis medium . tration to a subject. Thus, an unexpanded plurality of [0191 ] The hematopoietic cells that are ex vivo contacted hematopoietic cells can be ex vivo contacted as described with an agent as described herein and subsequently admin herein , thereby generating a plurality of modulated istered to a subject can be a heterogeneous population of hematopoietic cells as described herein , and administered to cells ( e . g . a plurality of heterogeneous hematopoietic cells ) . a subject prior to any substantial ex vivo cell division of the The plurality of heterogeneous hematopoietic cells can cells in the population , or prior to the time required for any include whole bone marrow , umbilical cord blood , mobi substantial cell division ex vivo . An unexpanded population lized peripheral blood , hematopoietic stem cells , hematopoi of cells can be ex vivo contacted as described herein and etic progenitor cells, and the progeny of hematopoietic stem administered to a subject prior to any substantial ex vivo and progenitor cells, including , for example , granulocytes mitosis of the cells in the population , or prior to the time ( e . g ., pro -myelocytes , myelocytes , metamyelocytes , neutro required for any substantial mitosis ex vivo . An unexpanded phils , eosinophils , basophils ) , erythrocytes (e .g . , reticulo plurality of hematopoietic cells can be ex vivo treated as cytes , erythrocytes ) , thrombocytes ( e . g . , megakaryoblasts , described herein and administered to a subject prior to the platelet producing megakaryocytes , platelets ) , and mono doubling time of the cells in the population . An unexpanded cytes ( e . g ., monocytes , macrophages ) . plurality of hematopoietic cells can be ex vivo treated as [0192 ] Contacting human cord blood , bone marrow cells , described herein and administered to a subject within 1 , 2 , or mobilized peripheral blood cells having hematopoietic 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , or 24 hours of treatment of the cells with an exogenous agent described herein that cells using the methods described herein , as well as any time increases PD -L1 and / or IDO - 1 , can increase the in vivo intervening these specific time points . An unexpanded plu immuno -regulatory properties of HSPC administered to a rality of hematopoietic cells can be ex vivo contacted as subject . Contacting human cord blood , bone marrow cells , described herein , and administered to a subject within about or mobilized peripheral blood cells having hematopoietic 2 hours of treatment of the cells . Further , an unexpanded cells with an exogenous agent described herein at a tem plurality of hematopoietic cells can be ex vivo contacted as perature greater than about room temperature can increase US 2018 /0112180 A1 Apr. 26 , 2018 14 the in vivo immuno -regulatory properties of the HSPC specification . In particular embodiments , modulated cells population administered to a subject. Contacting human find use in treating immunological or inflammatory disor cord blood , bone marrow cells , or mobilized peripheral ders . In some aspects , modulated cells treat immunological blood cells having hematopoietic cells with an exogenous or inflammatory disorders by inhibiting an immune response agent described herein for about 120 minutes at a tempera in a subject . As used herein , the phrase " immunological ture greater than about room temperature can increase the in disorder” includes, but is not limited to , autoimmune disor vivo immuno - regulatory properties of the hematopoietic cell ders , graft- versus host disease , and transplant rejection . population administered to a subject. 10197 ] The modulated cells of the invention find use in [ 0193 Contacting a purified population of Lin ( - )CD34 + treating any autoimmune disorder that responds to the HSPCs with an exogenous agent described herein can administration of a cell having increased PD -L1 and / or increase the in vivo expansion of the hematopoietic stem or IDO - 1 expression . Examples of autoimmune disorders that progenitor cell population administered to a subject. Con may be treated with the modulated cells include , but are not tacting a purified population of Lin ( - )CD34 + HSPCs with limited to , acute myocardial infarction , ischemic stroke , type an exogenous agent described herein at a temperature 1 diabetes , diabetes mellitus , multiple sclerosis , acute dis greater than about room temperature can increase the seminated encephalomyelitis , inflammatory demyelinating immuno - regulatory properties of the hematopoietic stem or diseases, lupus , Crohn ' s disease , osteoarthritis, rheumatoid progenitor cell population administered to a subject. Con arthritis , psoriatic arthritis , ulcerative colitis , dermatitis , tacting a purified population of Lin ( - )CD34 + HSPCs with irritable bowel syndrome, vitiligo , Graves ' disease , an exogenous agent described herein for about 120 minutes Hashimoto ' s disease , Addison 's disease, polymyositis , der at a temperature greater than about room temperature can matomyositis , myasthenia gravis , autoimmune hepatitis , increase immuno -regulatory properties of the hematopoietic Sjögren ' s syndrome, autoimmune gastritis , sclerosis , pso stem or progenitor cell population administered to a subject. riasis , asthma, or Wegener ' s granulomatosis . [0194 ] In various embodiments , the cells are not geneti [0198 ] In one embodiment, the modulated cells treat cally modified cells . In other embodiments , the cells are inflammatory conditions or disorders. As used herein , an genetically modified with a polynucleotide , such as, for inflammatory condition or disorder is a condition or disorder example a retroviral or lentiviral vector comprising a protein which has a basis in or component of inflammation . It is coding gene sequence . In some embodiments , the cell is recognized that some immunological disorders have an genetically modified to correct a genetic defect and in other inflammatory basis or component, and thus they are also embodiments , the cell is genetically modified to increase or categorized as inflammatory conditions , as discussed further decrease production of a wild - type or mutant protein . Poly below . Examples of inflammatory conditions which may be nucleotides used to increase expression of a protein in a cell treated by the administration of the modulated cells of the may comprise polynucleotide sequences to direct appropri invention include , but are not limited to , inflammation of the ate expression in the cell and a polynucleotide encoding the lungs , joints, connective tissue , eyes , nose , bowel, kidney , polypeptide sequence . Polynucleotides used to decrease liver , skin , central nervous system , endocrine system , vas expression of a protein in a cell may comprise polynucle cular system and heart . In certain embodiments , inflamma otide sequences that target polynucleotides encoding the tory conditions which may be treated by the current inven wild type polypeptide sequence for degradation . In some tion include inflammation due to the infiltration of embodiments , cells modulated according to the invention leukocytes or other immune effector cells into affected are purified cells or a population of cells comprising a tissue. Other relevant examples of inflammatory conditions mixture of cell types . In some embodiments of the invention , which may be treated by the present invention include hematopoietic stem and progenitor cells (HSPCs ) are modu inflammation caused by infectious agents , including , but not lated to increase PD -L1 and /or IDO - 1 expression . limited to , viruses, bacteria fungi and parasites . Hematopoietic stem cells are multipotent stem cells that give f0199 ). Inflammatory lung conditions include , but are not rise to all the blood cell types of an organism , including limited to , asthma, adult respiratory distress syndrome, myeloid ( e . g ., monocytes and macrophages, neutrophils , bronchitis , pulmonary inflammation , pulmonary fibrosis , basophils , eosinophils , erythrocytes , megakaryocytes/ plate and cystic fibrosis (which may additionally or alternatively lets , dendritic cells ), and lymphoid lineages ( e . g . , T- cells , involve the gastro - intestinal tract or other tissue( s ) ). Inflam B - cells , NK - cells ) , and others known in the art (See Fei, R . , matory joint conditions include rheumatoid arthritis , rheu et al. , U . S . Pat. No. 5 ,635 , 387 ; McGlave , et al ., U . S . Pat. No. matoid spondylitis , juvenile rheumatoid arthritis, osteoar 5 ,460 , 964 ; Simmons, P . , et al. , U . S . Pat . No. 5 ,677 , 136 ; thritis, gouty arthritis and other arthritic conditions. Eye Tsukamoto , et al. , U . S . Pat. No. 5 ,750 ,397 ; Schwartz, et al ., diseases with an inflammatory component include , but are U . S . Pat. No . 5 , 759 ,793 ; Tsukamoto , et al. , U . S . Pat. No . not limited to , uveitis (including iritis ), conjunctivitis, scleri 5 ,716 ,827 ) . Hematopoietic progenitor cells give rise to tis , keratoconjunctivitis sicca , and retinal diseases, includ committed hematopoietic progenitor cells that are capable of ing , but not limited to , diabetic retinopathy, retinopathy of generating the entire repertoire of mature blood cells over prematurity , retinitis pigmentosa , and dry and wet age the lifetimeof an organism . In some aspects of the invention , related macular degeneration . Inflammatory bowel condi CD34 + HSPCs are modulated to achieve increased PD -L1 tions include Crohn ' s disease , ulcerative colitis and distal and / or IDO - 1 expression . proctitis . [0195 ] III . Methods of Use 10200 ) Inflammatory skin diseases include , but are not [0196 ] Modulated cells can be useful in a variety of limited to , conditions associated with cell proliferation , such clinical settings , including cell transplantation , the treatment as psoriasis , eczema and dermatitis , (e . g ., eczematous der of disorders and diseases, and gene therapy . Accordingly , the matitides , topic and seborrheic dermatitis , allergic or irritant phrase “ a subject in need thereof” refers to an individualthat contact dermatitis , eczema craquelee , photoallergic derma is to be treated for a disease or disorder as disclosed in this titis , phototoxic dermatitis , phytophotodermatitis , radiation US 2018 /0112180 A1 Apr. 26 , 2018 15 dermatitis , and stasis dermatitis ) . Other inflammatory skin In one aspect, the patient receiving the modulated cells has diseases include , but are not limited to , scleroderma, ulcers not received a transplant. In one aspect , the patient receiving and erosions resulting from trauma, burns , bullous disorders , the modulated cells is not a candidate for hematopoietic or ischemia of the skin or mucous membranes, several forms transplant to reconstitute the hematopoietic compartment. In of ichthyoses, epidermolysis bullosae, hypertrophic scars , one non -limiting embodiment , modulated cells are admin keloids, cutaneous changes of intrinsic aging, photoaging , istered to a subject that has received no conditioning prior to frictional blistering caused by mechanical shearing of the administration of the cells . “ Conditioning ” as used herein is skin and cutaneous atrophy resulting from the topical use of meant to convey treatment typically administered prior to corticosteroids . Additional inflammatory skin conditions hematopoietic stem cell transplantation . Typically such con include inflammation of mucous membranes , such as che ditioning is performed with radio - or chemo - therapies . In ilitis , chapped lips, nasal irritation , mucositis and vulvovagi one aspect, the modulated cells are administered to a subject nitis . who has not had high - dose (myeloablative ) conditioning. In [ 0201] Inflammatory disorders of the endocrine system another aspect, the modulated cells are administered to a include , but are not limited to , autoimmune thyroiditis patient who has not had either high - dose or reduced - inten (Hashimoto ' s disease ) , Type I diabetes , Type II diabetes, and sity conditioning . In yet another aspect, the modulated cells acute and chronic inflammation of the adrenal cortex . are administered to a patient who has not had any of Inflammatory conditions of the cardiovascular system high -dose , reduced - intensity , or nonmyeloablative condi include , but are not limited to , coronary infarct damage , tioning peripheral vascular disease , myocarditis , vasculitis , revas [0210 ] In another embodiment, the modulated cells also cularization of stenosis , atherosclerosis , and vascular dis find use in treating immunological disorders that arise from ease associated with Type II diabetes . transplantation therapy, such as graft- versus - host disease [ 0202] Inflammatory conditions of the kidney include, but and transplant rejection , for example . Thus, modulated cells are not limited to , glomerulonephritis , interstitial nephritis , may be used to treat graft versus host disease or transplant lupus nephritis , nephritis secondary to Wegener ' s disease , rejection that results from a bone marrow transplant, solid acute renal failure secondary to acute nephritis , Goodpas organ transplant, or cell therapy ( e . g . any composition ture ' s syndrome, post -obstructive syndrome and tubular comprising isolated stem cells ) . Transplants in the context of ischemia . cell therapy , include, but are not limited to , the administra [0203 ] Inflammatory conditions of the liver include , but tion of genetically engineered cells that have been modified are not limited to , hepatitis (arising from viral infection , to produce a desired protein or polynucleotide in a subject. autoimmune responses , drug treatments , toxins, environ In aspects of the invention , modulated cells are administered mental agents , or as a secondary consequence of a primary to the subject before or at the time of transplantation so as disorder ), biliary atresia , primary biliary cirrhosis and pri to prevent graft - versus -host disease and /or transplant rejec mary sclerosing cholangitis . tion . Without being limited to any particular theory or 02041 Inflammatory conditions of the central nervous mechanism , treating a subject with modulated cells prior to system include, but are not limited to , multiple sclerosis and or at the time of transplantation dampens the immunological neurodegenerative diseases such as Alzheimer ' s disease , response in the transplant recipient and improves transplant Parkinson ' s disease , or dementia associated with HIV infec acceptance and engraftment . tion . [0211 ] In one non -limiting embodiment, modulated cells 10205 ) Other inflammatory conditions include periodontal are administered to a subject that has received a bone disease , tissue necrosis in chronic inflammation , endotoxin marrow transplant ( or cell therapy ) , wherein the transplant is shock , smooth muscle proliferation disorders, graft versus directed to hematopoietic engraftment or reconstitution . host disease , tissue damage following ischemia reperfusion Such subjects include, but are not limited to , subjects injury, and tissue rejection following transplant surgery. undergoing chemotherapy or radiation therapy for cancer, as [0206 ] The present invention further provides a method of well as subjects suffering from (e . g. , afflicted with ) non treating inflammation associated with wound healing, malignant blood disorders , particularly immunodeficiencies including post- surgical wound healing in a patient compris ( e . g . SCID , Fanconi' s anemia , severe aplastic anemia, or ing administering to said patient a composition comprising congenital hemoglobinopathies , or metabolic storage dis the modulated cells of the invention . eases , such as Hurler ' s disease , Hunter ' s disease , mannosi [ 0207 ] It should be noted that the modulated cells of the dosis , among others ) or cancer , particularly hematological current invention may be used to treat any disease which has malignancies, such as acute leukemia , chronic leukemia an inflammatory component, such as those diseases cited (myeloid or lymphoid ) , lymphoma (Hodgkin ' s or non above . Further, the inflammatory conditions cited above are Hodgkin ' s ), multiple myeloma, myelodysplastic syndrome, meant to be exemplary rather than exhaustive . or non -hematological cancers such as solid tumors ( includ [ 0208 ] Those skilled in the art would recognize that addi ing breast cancer, ovarian cancer, brain cancer , prostate tional inflammatory conditions ( e . g . , systemic or local cancer , lung cancer , colon cancer, skin cancer, liver cancer, immune imbalance or dysfunction due to an injury , an insult , or pancreatic cancer ). In some embodiments , the modulated infection , inherited disorder, or an environmental intoxicant cells are HSCs, or a modulated bone marrow transplant, are or perturbant to the subject' s physiology ) may be treated the administered for the purpose of providing hematopoietic modulated cells of the current invention . Thus , the methods engraftment or reconstitution in a subject, wherein the of the current invention may be used to treat any disease modulated cells or bone marrow avoid , or are made less which has an inflammatory component, including , but not susceptible to , graft -versus - host disease or transplant rejec limited to , those diseases cited above . tion . [ 0209 ] In one embodiment, the patient receiving the [ 0212 ] Subjects also include individuals that have modulated cells is not expected to have or need a transplant. received a bone marrow transplant or cell therapy in the US 2018 /0112180 A1 Apr. 26 , 2018 16 treatment of aplastic anemia ,myelodysplasia , thalassemaia , ( 0218 ] The amount of modulated hematopoietic cells sickle - cell disease or Wiskott - Aldrich syndrome. In some administered to the subject can be at least about 1x100 embodiments , the subject suffers from a disorder that is the cells /kg of bodyweight, at least about 1. 25x100 cells /kg of result of an undesired side effect or complication of another bodyweight, at least about 1. 5x100 cells /kg of bodyweight, primary treatment, such as radiation therapy, chemotherapy , at least about 1 .75x100 cells /kg of bodyweight , at least about or treatment with a bone marrow suppressive drug , such as 2x10 cells /kg ofbodyweight , at least about 2. 5x10 cells/ kg zidovadine, chloramphenical or gangciclovir . Such disorders of bodyweight, at least about 3x100 cells /kg of bodyweight, include neutropenias, anemias, thrombocytopenia , and at least about 4x10° cells /kg of bodyweight, at least about immune dysfunction . 5x100 cells /kg of bodyweight, at least about 1x10 ' cells/ kg [ 0213 ] Administration of an " amount" of modulated cells of bodyweight, at least about 1 .5x107 cells /kg of body to a subject refers to administration of an amount effective , weight, at least about 2x10 ' cells/ kg of bodyweight, at least ” to achieve the desired therapeutic or prophylactic result , about 2 . 5x107 cells /kg of bodyweight, at least about 3x10 including without limitation , treatment of the subject. A cells /kg of bodyweight, at least about 5x10 ' cells /kg of “ therapeutically effective amount ” of cells for purposes bodyweight, at least about 7x10 ' cells/ kg of bodyweight, at herein is thus determined by such considerations as are least about 1x108 cells /kg of bodyweight, at least about known in the art, and may vary according to factors such as 3x108 cells /kg of bodyweight, at least about 5x108 cells /kg the disease state , age, sex , and weight of the individual, and of bodyweight, at least about 7x108 cells /kg of bodyweight, the ability of the cells to elicit a desired response in the at least about 1x10 cells/ kg of bodyweight, at least about individual. The term “ therapeutically effective amount” 3x10° cells /kg of bodyweight, at least about 5x109 cells / kg includes an amount that is effective to treat” a subject ( e .g ., of bodyweight , at least about 7x109 cells /kg of bodyweight, a patient) . A therapeutically effective amount is also one in or at least about 3x10 ' cells /kg of bodyweight. which any toxic or detrimental effects of the cells are [0219 ] In another embodiment, the amount of modulated outweighed by the therapeutically beneficial effects . hematopoietic cells administered to a subject is the amount of hematopoietic cells in a partial or single cord ofblood , or [ 0214 ] A “ prophylactically effective amount” refers to an about 1x105 cells to about 2x108 cells ; about 1 . 0x10 cells amount of cells having therapeutic potential that is effective to about 2x10 ' cells ; about 2x100 cells to about 1x10 ' cells , to achieve the desired prophylactic result . Typically but not about 2x100 cells to about 7x10 cells , about 2x100 cells to necessarily , since a prophylactic dose is used in subjects about 5x10 cells , or about 2x10 cells to about 3x10 cells . prior to or at an earlier stage of disease , the prophylactically [ 0220 ] The modulated cells of the present invention may effective amount is less than the therapeutically effective be administered to a subject at one or more times . For amount. instance , the present methods contemplate one , 2 , 3 , 4 , 5 , 6 , [ 0215 ] The amount of modulated hematopoietic cells 7 , 8 , 9 , 10 , or more administrations . In one embodiment, administered to a subject can be , for example , the amount of repeated administrations may persist until one or more HSPC in a partial or single cord of blood . The amount of symptoms of an autoimmune disorder are decreased . In modulated hematopoietic cells can be at least 2x100 cells , at another embodiment, repeated administrations may persist least 2 .5x10 cells , at least 3x100 cells , at least 4x109 cells , for the lifetime of the subject to maintain a certain level of at least 5x100 cells , at least 1x107 cells , at least 1 .5x107 symptoms. cells , at least 2x10 ' cells , at least 2 .5x10 ' cells , or at least 0221 ] In one embodiment, the administrations may be an 3x10 cells . interval ranging from twice every week to once every six [0216 ] The amount of modulated hematopoietic cells months. For instance , the administrations may be every two administered to a subject can be about 2x10 cells, about weeks, every three weeks, every four weeks, monthly , every 3x10 cells , about 5x10° cells , about 7x100 cells , about other month , every three months, every four months, or 10x10 cells, about 15x10 cells , about 1 . 7x10 cells, about every six months . In one embodiment, the interval between 2 .0x10 ' cells about 2 .5x10 ' cells , about 3 .0x10 ' cells , about administrations of modulated cells is every two weeks. In 5 .0x107 cells , about 1. 0x108 cells , about 3 .0x108 cells , about one embodiment the interval between administrations of 5 . 0x108 cells , about 1 . 0x10 cells , about 3 . 0x10° cells , about modulated cells is every six weeks . 5 .0x109 cells , or about 1. 0x1010 cells . [0222 ] In one embodiment, the patient may be adminis [ 0217] The amount of modulated hematopoietic cells tered an initial therapy cycle , or prescribed therapy regimen , administered to the subject can be, for example , about 2x106 with an initial dose at an initial interval and thereafter be cells to about 2x1010 cells ; about 2x10 cells to about 7x109 administered another therapy cycle with a maintenance dose cells ; about 2x10 cells to about 5x107 cells ; about 2x106 and maintenance interval. In one embodiment, the initial cells to about 3x10 ' cells ; or about 2x100 cells to about dose is a higher dose than the maintenance dose . Alterna 2 .5x10 ' cells . The amount ofmodulated hematopoietic cells tively , the initial dose may be lower than the maintenance administered to the subject can , for example , be about 2x106 dose , as potential side - effects are observed . Further, in one cells . The amount of modulated hematopoietic cells admin embodiment the maintenance interval may be longer than istered to the subject can , for example, be about 5x100 cells . the initial interval in the therapy cycle , such as with The amount of modulated hematopoietic cells administered " booster ” administrations. In another embodiment, the to the subject can , for example , be about 1x107 cells . The maintenance interval may be shorter than the initial interval . amount of modulated hematopoietic cells administered to [0223 ] Suitable methods for administering modulated the subject can , for example , be about 5x107 cells . The cells used in the methods described herein include parenteral modulated hematopoietic cells can be administered to the administration , including , but not limited to methods of subject in an amount less than about 2x108 cells . The intravascular administration , such as intravenous and modulated hematopoietic cells can be administered to the intraarterial administration . Additional illustrative methods subject in an amount less than about 2x10 ' cells . for administering cells of the invention include intramuscu US 2018 /0112180 A1 Apr. 26 , 2018 17 lar, intrathecal, intracapsular, intraorbital, intracardiac , intra Following cell treatments , gross mRNA levels were normal dermal, intraperitoneal, transtracheal , subcutaneous ( subder ized against gross mRNA levels from the untreated cells mal) , subcuticular, intraarticular, subcapsular, subarachnoid , before RT- PCR . Levels of PD - L1 or IDO - 1 mRNA were intraspinal and intrastemal injection and infusion . quantified from PICOPURE® isolated mRNA ( Life Tech 10224 ] In one embodiment, the modulated cells are admin nologies) using an Assay on Demand TAQMAN® RT -qPCR istered locally . In another embodiment, the modulated cells assay (Life Technologies ). are administered systemically . [0232 ] Results of PD - L1 Expression After Modulation are 0225 ] In one embodiment, the route of administration is shown in Table 1 . not a route used for hematopoietic transplant. For instance , hematopoietic transplant is generally systemic intravenous TABLE 1 infusion . Thus, local administrations or non - intravenous administrations are not routes used for hematopoietic trans PD - L1 Expression after Modulation With Agent plant. PD -L1 [0226 ] Therapeutic advantages may be realized through Compound name Class/ MOA % Viability fold change combination regimens including the present compositions. Those skilled in the art will appreciate that the modulated Tyrphostin AG 835 Protein tyrosine 61. 3 32. 57 kinase inhibitor cells described herein may be administered as part of a Vigabatrin GABA 67 16 . 76 combination therapy approach to the treatment of an immu transaminase nomodulatory disease or an inflammatory condition . For inhibitor instance , the presentmodulated hematopoietic cells express Betamethasone Glucocorticoid 86 . 8 4 . 16 Fluocinolone Glucocorticoid 82. 9 10 . 58 ing increased levels of PD - L1 and /or IDO - 1 may be com acetonide bined with a second active agent. In combination therapy the Nitrofural Antibacterial 87. 2 10 . 28 respective agents may be administered simultaneously , or Clobetasol Glucocorticoid 83 9 .27 sequentially in any order. When administered sequentially , it propionate Clocortolone Glucocorticoid 84 . 9 8 .64 may be preferred that the components be administered by pivalate the same route . Fluphenazine Dopamine 86 7 . 58 [0227 ] Alternatively , the components may be formulated receptor together in a single dosage unit as a combination product. antagonist Suitable agents which may be used in combination with the Flumethasone Glucocorticoid 89 . 6 7 .58 compositions of the present invention will be known to those of ordinary skill in the art . [0233 ] FIG . 1 shows results of PD -L1 gene expression [0228 ] In certain embodiments , the present invention pro levels as the mean of three individual donors of CD34 + cells vides a kit comprising: a ) one or more single dosage forms treated with a single exogenous agent ( A ) 10 uM Dexam comprising a population ofmodulated hematopoietic cells of ethasone ; ( B ) 1000 U /mL Interferon beta (IFNB ) ; (C ) 5 the invention ; b ) one or more single dosage forms of second ng /mL Interferon gamma (IFNY ) ; ( D ) 10 ug /mL High active agent for use in a combination therapy and c) instruc Molecular Weight Polyinosinic - polycytidylic acid (Poly tions for the administration of the population of modulated ( I : C ) ) or multiple exogenous agents ; ( E ) 1000 U /mL IFNB , hematopoietic cells of the invention and the second active 5 ng/ mL IFNy, and 10 ug /mL Poly ( I : C ) . FIG . 4 shows agent . results ofmodulation with additional glucocorticoids for 24 [0229 ] In one aspect, the present invention provides a kit hours at 37° C . comprising : a ) a pharmaceutical formulation (e . g ., one or more single dosage forms) comprising a population of [0234 ] Results of IDO - 1 Expression after modulation are modulated hematopoietic cells of the invention ; and b ) shown in Table 2 . instructions for the administration of the pharmaceutical formulation e .g ., for treating or preventing a disorder or TABLE 2 condition as discussed above , e . g . , inflammatory disease . IDO - 1 Expression After Modulation With Agent [0230 ] Particular embodiments of the present invention IDO - 1 now will be described more fully by the following examples . Exogenous Agent % Viability This invention may, however, be embodied in many different Class/ MOA fold change forms and should not be construed as limited to the embodi Gemcitabine Antineoplastic 81. 4 30 . 13 Fluphenazine Dopamine receptor 86 14 . 19 ments set forth herein ; rather, these embodiments are pro antagonist vided so that this disclosure will be thorough and complete , Isometheptene Adrenergic receptor 83. 7 6 .98 and will fully convey the scope of the invention to those mucate agonist skilled in the art . Dihydrostrepto Ribosomal protein 84 .5 6 . 19 mycin sulfate synthesis inhibitor Protriptyline Adrenergic 79 . 4 5 . 74 EXAMPLE 1 reuptake inhibitor Telenzepine M1muscarinic 88. 9 4 . 82 Elevated Gene Expression Levels of PD - L1 antagonist Cyclobenzaprine Serotonin receptor 72 . 7 4 .65 ( CD274 ) or IDO - 1 in Human Stem and Progenitor antagonist Cells Letrozole Antineoplastic 81. 3 4 . 38 Fludarabine Antineoplastic 82 .5 4 .22 [ 0231 ] Human CD34 + stem and progenitor cells isolated 4 - aminosalicylic from mobilized peripheral blood from three donors were ex NF -kB inhibitor 85 . 3 4 .07 vivo treated in STEMSPAN® (StemCell Technologies) for acid 24 hours at 37° C . with one or more exogenous agents . US 2018 /0112180 A1 Apr. 26 , 2018 18

[0235 ] FIGS . 5A - D show results of the IDO - 1 gene [0240 ] Exogenous Agents : expression levels , as the mean of three individual donors of [ 0241 ] 1000 U /mL IFNB ; CD34 + cells treated with a single exogenous agent ( A ) 1000 [0242 ] 5 ng /mL IFNy; U /mL Interferon beta ( IFNB ) ; ( B ) 5 ng /mL Interferon 10243 ] 10 ug /mL Poly ( I : C ) ; gamma ( IFNY) ; (C ) 10 ug/ mL High Molecular Weight Polyinosinic - polycytidylic acid (Poly ( I : C ) ) or multiple [0244 ] 1000 U /mL IFNB + 5 ng/ mL IFNY; exogenous agents ; ( D ) 1000 U /mL IFNB , 5 ng/ mL IFNy, and [0245 ] 5 ng/ mL IFNy+ 10 ug /mL Poly ( I : C ) ; or 10 ug /mL Poly ( I : C ) . FIG . 6 shows incubation for 24 hours [0246 ] 1000 U /mL IFNB + 5 ng/ mL IFNy+ 10 ug/ mL Poly at 37° C . with additional exogenous agents , including anti ( I : C ) . neoplastic agents , dopamine receptor antagonists and others. [ 0247 ] FIG . 7 shows the average fold -change of PD - L1 by median fluorescence intensity (MFI ) relative to the untreated EXAMPLE 2 sample for three individual donors of CD34 + cells . Elevated Levels of PD -L1 (CD274 ) or IDO - 1 EXAMPLE 5 Surface Protein on Human Stem and Progenitor Cells Post -Modulation Storage and PD - L1 Expression [0236 ] Human CD34 + stem and progenitor cells (HSC ) (0248 ] Human CD34 + stem and progenitor cells (HSCs ) isolated from mobilized peripheral blood were ex vivo isolated from mobilized peripheral blood were ex vivo treated in STEMSPAN® serum - free expansion medium treated in STEMSPAN® serum -free expansion medium ( SFEM ) ( StemCell Technologies ) with stem cell factor (SFEM ) (StemCell Technologies ) with stem cell factor ( SCF ) , Flt - 3 - Ligand , thrombopoietin ( TPO ), Interleukin - 6 ( SCF) , Flt - 3 -Ligand , thrombopoietin ( TPO ), Interleukin -6 ( IL - 6 ) for 24 hours at 37° C . with one or more exogenous ( IL - 6 ) for 24 hours at 37° C . with one or more exogenous agents . Following cell treatments , levels of PD -L1 or IDO - 1 agents . Following cell treatments , the media /reagents were cell surface protein were measured on the viable CD34 + washed , the cells were resuspended in either HBSS ( for the cells by staining the cells with anti -CD34 , anti - PD -L1 or “ immediate ” group ) , SFEM , or appropriate cryogenic anti - IDO - 1 , and 7 - Aminoactinomycin D ( 7 - AAD ) . Data was media . Subsequently , the cells were either measured ( “ im acquired on a FORTESSA® X - 20 (Becton Dickinson ) and mediate” ) or placed for 24 hours at 37° C ., 4° C ., or were analyzed using FLOWJO? ( TreeStar ) . cryopreserved . After 24 hours, the cells were thawed or [ 0237 ] FIG . 2 shows the average fold - change of PD -L1 by allowed to return to room temperature and levels of PD - L1 median fluorescence intensity (MFI ) relative to the untreated cell surface protein were measured on the viable CD34 + sample for three individual donors of CD34 + cells treated cells by staining the cells with anti -CD34 or anti - PD -L1 , and with a single exogenous agent (A ) 1000 U /mL IFN # 2 (B ) 7 -Aminoactinomycin D ( 7 -AAD ) . Data was acquired on a 5 ng /mL IFNY ( C ) 10 ug /mL Poly ( I : C ) or multiple exog FORTESSA® X - 20 (Becton Dickinson ) and analyzed using enous agents D ) 1000 U /mL IFNB , 5 ng /mL IFNy, and 10 FLOWJO? ( TreeStar ) . yg /mL Poly ( I: C ) . [0249 ] FIG . 8 demonstrates that post- modulation , the modulated cells are viable and express PD -L1 when main EXAMPLE 3 tained in a variety of conditions . Thus, the modulated cells T Cell Proliferation is Reduced in the Presence of may be stored post modulation . Modulated HSPC EXAMPLE 6 [0238 ] HSCs were incubated 24 hours in media containing 1000 U /mL IFNB , 5 ng/ mL IFNy, and 10 ug /mL Poly I: C or Immunosuppression in Matched and Unmatched media containing vehicle . The cells were then washed and CD34 + Cell Populations combined at a 1 : 1 ratio with autologous T cells . T cell [0250 ] Human CD34 + stem and progenitor cells isolated mitogen was added and cocultures were incubated for 5 from mobilized peripheral blood were ex vivo treated in days . FIG . 3 shows T cell proliferation as measured by flow StemSpan (StemCell Technologies ) supplemented with stem cytometry. cell factor ( SCF ) , Flt - 3 -Ligand , thrombopoietin ( TPO ) , Interleukin - 6 ( IL -6 ) and with IFNB + IFNY (Gamma +Beta ) EXAMPLE 4 or IFNB + IFNy + Poly ( I : C ) (aka , the “ Trifecta ” group ) for 6 , 24 , and 48 hours at 37° C . Following cell treatments , CD34 Time Course of PD - L1 Expression cells were washed and co - cultured with CD3/ 28 bead acti [ 0239] Human CD34 + stem and progenitor cells (HSCs ) vated T cells . At the completion of a 5 day co - culture , the isolated from mobilized peripheral blood were ex vivo number of viable CD4 and CD8 T cells was quantified by treated in STEMSPAN® serum - free expansion medium staining the cells with anti - CD4 , anti -CD8 , and 7 Amino ( SFEM ) ( StemCell Technologies ) with stem cell factor actinomycin D ( 7 - AAD ) . Data was acquired on a Fortessa ( SCF ) , Flt - 3 - Ligand , thrombopoietin ( TPO ), Interleukin -6 X - 20 (Becton Dickinson ) and analyzed using Flow Jo ( Tree ( IL - 6 ) for 6 , 24 , or 48 hours at 37° C . with one or more Star ). The data is expressed as the fold change in the number exogenous agents . Following cell treatments, levels of of CD4 + and CD8 + T cells for each co - culture condition PD - L1 cell surface protein were measured on the viable normalized to the number of T cells in the DMSO treated CD34 + cells by staining the cells with anti -CD34 , anti - PD CD34 condition . L1 and 7 - Aminoactinomycin D ( 7 - AAD ) . Data was [0251 ] FIGS. 9A and 9B Demonstrate that ex vivo treated acquired on a FORTESSA® X -20 (Becton Dickinson ) and human stem and progenitor cells suppress the proliferation analyzed using FLOWJOR ( TreeStar ) . of both autologous and allogeneic T cells. US 2018 /0112180 A1 Apr. 26 , 2018 19

EXAMPLE 7 reporter expression and the cells were co - cultured with CD3 /28 bead activated autologous or allogeneic T cells in Modulation of PD -L1 with PD -L1 Polynucleotides the presence or absence of the IDO - 1 inhibitor 1 -methyl - D and Immunosuppression tryptophan ( 1MT) . Media from transduced HSC were added [ 0252] Human CD34 + stem and progenitor cells isolated to a population of human T - cells 1 : 1 by volume and incu from mobilized peripheral blood were transduced with len bated . At the completion of a 5 day incubation , the number tiviral vectors for the transgenic expression of human PD -L1 of viable CD4 and CD8 T cells was quantified by staining in StemSpan (StemCell Technologies) supplemented with the cells with anti -CD4 , anti -CD8 , and 7 Aminoactinomycin stem cell factor ( SCF ) , Flt- 3 - Ligand , thrombopoietin ( TPO ) , D ( 7 - AAD ) . Data was acquired on a Fortessa X - 20 (Becton Interleukin - 6 ( IL - 6 ) for 24 hours at 37° C . Transduced Dickinson ) and analyzed using Flow Jo ( TreeStar ) . CD34 + cells were isolated by flow cytometry using GFP [0257 ] The data is expressed as the fold change in the reporter expression and the transduced (PD -L1 + ) or untrans number of CD4 + and CD8 + T cells for each co -culture duced (PD - L1 - ) cells were co -cultured with CD3/ 28 bead condition normalized to the number of T cells in the untrans activated T cells . At the completion of a 5 day co -culture , the duced CD34 condition . number of viable CD4 and CD8 T cells was quantified by 0258 ] Results : staining the cells with anti -CD4 , anti -CD8 , and 7 Amino [0259 ] As shown by FIG . 12 , T cells treated with media actinomycin D ( 7 -AAD ) . Data was acquired on a Fortessa from a modulated population of hematopoietic cells dem X - 20 (Becton Dickinson ) and analyzed using Flow Jo ( Tree onstrating upregulated IDO - 1 expression significantly sup Star ) . The data is expressed as the fold change in the number pressed T cell proliferation . The suppression of T cells of CD4 + and CD8 + T cells for each co - culture condition demonstrates that modulated populations of cells suppress T normalized to the number of T cells in the DMSO treated cell responses in a contact- independent manner . CD34 condition . [0253 ] FIG . 10 demonstrates that genetic overexpression EXAMPLE 10 of PD - L1 in human CD34 + stem and progenitor cells Glucocorticoid Treated CD34 + Cells Decrease T enhances suppression of T cell proliferation . Cell Proliferation and Effector Function in a Model EXAMPLE 8 of Type 1 Diabetes [0260 ] Methods Genetic overexpression of IDO - 1 with IDO1 [0261 ] Modification of Hematopoietic Cells : Polynucleotides and Immunosuppression 0262 ] A population of CD34 + cells is contacted in HSC media with a number of different glucocorticoids for 24 [0254 ] Human CD34 + stem and progenitor cells isolated hours at 37° C . Such contact significantly upregulates the from mobilized peripheral blood were transduced with len expression of the T cell co - inhibitory protein , PDL - 1 . The tiviral vectors for the transgenic expression of human IDO1 PD - 1 /PDL - 1 immune checkpoint pathway plays an impor in StemSpan (StemCell Technologies) supplemented with tant role in inhibiting the proliferation of autoreactive T stem cell factor (SCF ) , Flt - 3 -Ligand , thrombopoietin ( TPO ) , cells , which in turn reduces autoimmunity and promotes Interleukin - 6 ( IL - 6 ) for 24 hours at 37° C . Transduced self -tolerance . The population of CD34 + cells is washed and CD34 + cells were isolated by flow cytometry using GFP re - suspended in HBSS before injection to remove traces of reporter expression and the cells were co - cultured with the glucocorticoids and culture media . CD3/ 28 bead activated autologous or allogeneic T cells in [0263 ] In Vivo Immunosuppression : the presence or absence of the IDO1 inhibitor 1 -methyl - D [0264 ] In order to determine the immune - suppressive tryptophan ( 1MT) . At the completion of a 5 day co -culture , potential of human CD34 + cells on diabetogenic T cells in the number of viable CD4 and CD8 T cells was quantified vivo , 8 week old immuno - deficient NSG -HLA - A2 /HHD by staining the cells with anti - CD4 , anti - CD8 , and 7 Amino mutant mice (which express the human HLA class 1 heavy actinomycin D ( 7 - AAD ) . Data was acquired on a Fortessa and light chains ) are injected intraperitoneally ( i. p . ) with X - 20 (Becton Dickinson ) and analyzed using Flow Jo ( Tree 10x10 HLA - A2 + peripheral blood mononuclear cells ( PB Star) . The data is expressed as the fold change in the number MCs ) from type 1 diabetic ( T1D ) patients . 3 days after the of CD4 + and CD8 + T cells for each co -culture condition adoptive transfer of the TID PBMCs , the animals are normalized to the number of T cells in the untransduced injected with either Hanks Balanced Salt Solution (HBSS ) , CD34 condition . 10º CD34 + cells isolated from mobilized peripheralblood of [0255 ] FIG . 11 demonstrates that genetic overexpression healthy patients grown 24 hours in hematopoietic stem cell of IDO - 1 in human CD34 + stem and progenitor cells (HSC ) media ( untreated - CD34 ) , or 106 CD34 + cells grown enhances suppression of T cell proliferation . 24 hours in HSC media supplemented with a glucocorticoid (GC - CD34 ) ( i. e ., the modulated cells) . EXAMPLE 9 [0265 ] On days 7 and 14 post injection of the PBMCs, the spleen , bone marrow and pancreas are harvested . Human Contact Independent Effect ofModulated Cells specific gene expression profiling , as well as flow cytometric [ 0256 ] Human CD34 + stem and progenitor cells isolated analysis of the antibody stained cell preparation , is used to from mobilized peripheral blood were transduced with len quantify the accumulation of human CD34 + and T cells in tiviral vectors for the transgenic expression ofhuman IDO - 1 those tissues. Furthermore , the immuno -phenotype and in StemSpan ( StemCell Technologies ) supplemented with effector function of the human T cells residing in the stem cell factor ( SCF ) , Flt - 3 - Ligand , thrombopoietin ( TPO ) , pancreas is assessed by flow cytometry , to characterize the Interleukin - 6 ( IL -6 ) for 24 hours at 37° C . Transduced differentiation and activation profiles of human T cells CD34 + cells were isolated by flow cytometry using GFP present in the target tissues . US 2018 /0112180 A1 Apr. 26 , 2018

[0266 ] Finally , using a separate cohort of mice , the pan ( ii ) comprise a prostaglandin pathway agonist and a creas is collected and prepared for immunofluorescence glucocorticoid . analysis of the Islets of Langerhans to determine B - cell 9 - 12 . ( canceled ) insulin production and the nature of the inflammatory infil trate . As above , human specific gene expression profiling 13 . The method according to claim 8 , wherein and flow cytometric analysis is used to quantify the accu ( i) the prostaglandin pathway agonist is selected from mulation of human CD34 + and T cells in those tissues . PGE2, dmPGE2, 15 (S ) - 15 -methyl PGE2, 20 -ethyl Immuno -phenotype and effector function of the human T PGE2, 8 - iso - 16 - cyclohexyl - tetranor PGE2 , 16 , 16 - dim cells residing in the pancreas is assessed by flow cytometry, ethyl PGE2 (“ dmPGE2" ) , p - (p - acetamidobenzamido ) to characterize the differentiation and activation profiles of phenyl ester, 11 -deoxy - 16 , 16 -dimethyl PGE2 , 9 -de human T cells present in the target tissues. oxy - 9 -methylene - 16 , 16 - dimethyl PGE2, 9 - deoxy - 9 [0267 ] Results: methylene PGE2, 9 -keto Fluprostenol, 5 - trans PGE2, 10268 ] T cell proliferation and effector function is signifi 17 - phenyl- omega - trinor PGE , PGE , serinol amide , cantly reduced in the pancreas of the T1D PBMC animals PGE , methyl ester, 16 - phenyl tetranor PGE2, 15 ( S ) injected with GC -CD34 cells both at day 7 and day 14 15 -methyl PGE2, 15 ( R ) - 15 -methyl PGE2, 8 - iso - 15 compared to vehicle - treated CD34s. This will be evidenced keto PGE2, 8 - iso PGE , isopropyl ester , 8 - iso - 16 - cyclo by a decrease in the proliferation of the human T cells and hexyl- tetranor PGE2, 20 -hydroxy PGE2, 20 - ethyl a reduction in their capacity to secrete INFy after re PGE2, 11 -deoxy PGE , nocloprost , sulprostone, stimulation . In addition , as a result of the GC - CD34 medi butaprost, 15- keto PGE2, and 19 ( R ) hydroxy PGE2 ; or ated reduction of pancreatic T cell cytotoxicity , pancreatic ( ii ) the glucocorticoid is selected from (1 ) medrysone , alclometasone , alclometasone dipropionate, amcinon B -cells have an increase in insulin production . ide , beclometasone , beclomethasone dipropionate , [ 0269 ] In summary , glucocorticoid treated CD34 cells are betamethasone, betamethasone benzoate , betametha a more effective treatment of T cell mediated pancreatic sone valerate , budesonide , ciclesonide , clobetasol, clo B - cells toxicity compared to un - treated CD34 cells in this betasol butyrate, clobetasol propionate, clobetasone, humanized TiD model. clocortolone , cloprednol , cortisol, cortisone, cortivazol, 10270 ] The various embodiments described above can be deflazacort , desonide , desoximetasone, desoxycortone , combined to provide further embodiments . All of the U . S . desoxymethasone, dexamethasone , diflorasone, patents , U . S . patent application publications, U . S . patent diflorasone diacetate , diflucortolone , diflucortolone applications , foreign patents, foreign patent applications and valerate , difluorocortolone , difluprednate , fluclorolone, non -patent publications referred to in this specification and / fluclorolone acetonide , fludroxycortide , flumethasone , or listed in the Application Data Sheet are incorporated flumethasone pivalate , flunisolide , flunisolide hemihy herein by reference, in their entirety . Aspects of the embodi drate , fluocinolone , fluocinolone acetonide , fluocinon ments can be modified , if necessary to employ concepts of ide , fluocortin , fluocoritin butyl, fluocortolone , fluoro the various patents , applications and publications to provide cortisone , fluorometholone, fluperolone, fluprednidene, yet further embodiments. fluprednidene acetate , fluprednisolone , fluticasone, flu [ 0271 ] These and other changes can be made to the ticasone propionate , formocortal, halcinonide, halo embodiments in light of the above - detailed description . In metasone , hydrocortisone , hydrocortisone acetate , general, in the following claims, the terms used should not hydrocortisone aceponate , hydrocortisone buteprate , be construed to limit the claims to the specific embodiments hydrocortisone butyrate , loteprednol, meprednisone , disclosed in the specification and the claims, but should be 6a -methylprednisolone , methylprednisolone, methyl construed to include all possible embodiments along with prednisolone acetate , methylprednisolone aceponate , the full scope of equivalents to which such claims are mometasone , mometasone furoate , mometasone entitled . Accordingly, the claims are not limited by the furoate monohydrate , paramethasone , prednicarbate , disclosure . prednisolone , prednisone, prednylidene , rimexolone, 1 . A method for modulating a population of cells com tixocortol, triamcinolone , triamcinolone acetonide and prising : incubating the population of cells comprising ulobetasol, as well as combinations thereof; or ( 2 ) hematopoietic stem and / or progenitor cells (HSPCs ) ex vivo betamethasone , clobetasol proprionate , flumethasone, in the presence of one or more small molecules capable of flucinolone acetonide , medrysone , hydrocortisone , tri increasing PD -L1 and /or IDO - 1 expression to obtain a population of cells having increased expression of PD -L1 amcinolone, alclometasone , and dexamethasone. and/ or IDO - 1 . 14 - 21 . (canceled ) 2 - 6 . (canceled ) 22 . The method according to claim 1 , wherein the popu 7 . The method according to claim 1 , wherein the increase lation of cells in PD - L1 and /or IDO - 1 expression in the modulated cells is ( i ) comprises at least about 50 % , at least about 60 % , at about 3 - fold to about 80 - fold compared to cells not incu least about 70 % , at least about 80 % , at least about 85 % , bated with the small molecule (s ) . at least about 90 % , at least about 95 % , at least about 8 . The method according to claim 1 , wherein the one or 98 % , or at least about 99 % HSPCs ; or more small molecules ( ii ) is enriched for CD34 + HSPCs prior to contact with the ( i) are selected from the group consisting of a prostaglan small molecule ( s ) . din pathway agonist , a glucocorticoid , an antineoplas 23 -25 . ( canceled ) tic , a dopamine receptor agonist, isometheptene 26 . A method of treating an immunological or inflamma mucate , dihydrostreptomycin sulfate , protriptyline , tory disorder comprising incubating a population of HSPCs telenzepine, cyclobenzaprine , 4 - aminosalicylic acid , ex vivo in the presence of one or more small molecules and combinations thereof; or capable of increasing PD -L1 and / or IDO - 1 expression and US 2018 /0112180 A1 Apr. 26 , 2018

administering a therapeutically effective amount of the mechanical shearing of the skin , cutaneous atrophy population of cells to a patient in need thereof. resulting from the topical use of corticosteroids , che 27 - 32 . (canceled ) ilitis , chapped lips , nasal irritation , mucositis and vul 33 . The method according to claim 26 , wherein the vovaginitis; population of cells (vi ) the inflammation of the endocrine system is selected (i ) is allogeneic to the patient from autoimmune thyroiditis (Hashimoto ' s disease ) , ( ii ) is HLA matched or partially HLA matched with the Type I diabetes , Type II diabetes, and acute and chronic patient inflammation of the adrenal cortex ; ( iii) comprises haplotyped HSPCs ; or ( vii ) the inflammation of the cardiovascular system is ( iv ) comprises about 2x106 to about 2x1010 CD34 + selected from coronary infarct damage, peripheral vas HPSCs. cular disease , myocarditis , vasculitis , revascularization 34 - 37 . (canceled ) of stenosis , artherosclerosis , and vascular disease asso 38 . The method according to claim 26 , wherein the ciated with Type II diabetes ; method comprises more than one administration of a thera ( viii ) the inflammation of the kidney is selected from peutically effective amount of cells ; wherein optionally glomerulonephritis , interstitial nephritis , lupus nephri ( i ) the frequency of administrations ranges from about tis , nephritis secondary to Wegener' s disease , acute twice a week to about every six months ; or renal failure secondary to acute nephritis , Goodpas ( ii ) the initial administration is a higher number of cells ture ' s syndrome , post - obstructive syndrome and tubu than a subsequent administration . lar ischemia ; 39 -40 . (canceled ) ( ix ) the inflammation of the liver is selected from hepa 41 . The method according to claim 26 , wherein titis , biliary atresia , primary biliary cirrhosis and pri ( i ) the immunological disorder is ( a ) an autoimmune mary sclerosing cholangitis ; or disorder selected from acute myocardial infarction , (x ) the inflammation of the central nervous system is ischemic stroke , type 1 diabetes , diabetes mellitus , selected from multiple sclerosis and neurodegenerative multiple sclerosis , acute disseminated encephalomyeli diseases such as Alzheimer ' s disease , Parkinson ' s dis tis , inflammatory demyelinating diseases, lupus, ease , or dementia associated with HIV infection . Crohn ' s disease , osteoarthritis , rheumatoid arthritis , 65 - 74 . (canceled ) psoriatic arthritis , ulcerative colitis , dermatitis , irritable 75 . The method according to claim 26 , wherein the bowel syndrome, vitiligo , Graves ' disease , Hashimo administration is local . to ' s disease , Addison ' s disease , polymyositis , dermato 76 - 77 . (canceled ) myositis , myasthenia gravis , autoimmune hepatitis , 78 . A pharmaceutical composition comprising a popula Sjögren ' s syndrome, autoimmune gastritis, sclerosis , tion of modulated cells comprising HSPCs, and a pharma psoriasis , asthma, Wegener ' s granulomatosis ; or (b ) ceutically acceptable carrier; graft vs host disease or transplant rejection ; or wherein the modulated cells have an increased level of ( ii ) the inflammatory disorder is selected from inflamma PD -L1 and /or IDO - 1 expression that is increased about tion of the lungs, joints , connective tissue , eyes , nose , 3 fold to about 80 fold compared to a level of PD -L1 bowel , kidney , liver, skin , central nervous system , and /or IDO - 1 expression in a population of non -modu endocrine system , cardiovascular system and heart. lated cells ; wherein optionally the pharmaceutical com 42 - 44 . ( canceled ) position is formulated for a local or non - intravenous 45 . The method according to claim 26 , wherein the patient administration . has not undergone high -dose , reduced - intensity , or nonmy 79 -88 . (canceled ) eloablative conditioning. 89 . A kit comprising the pharmaceutical composition 46 -63 . (canceled ) according to claim 78 and a second active agent for use in 64 . The method according to claim 41, wherein a combination therapy. ( i) the inflammation of the lung is selected from asthma, 90 . The method according to claim 13 , wherein the adult respiratory distress syndrome, bronchitis , pulmo prostaglandin pathway agonist is 16 , 16 -dmPGE2 or PGE2 , nary inflammation , pulmonary fibrosis , and cystic and the glucocorticoid is dexamethasone . fibrosis ; 91 . A method of administering cells comprising : ( ii ) the inflammation of the joints is selected from rheu administering the modulated cells according to claim 1 to matoid arthritis , rheumatoid spondylitis, juvenile rheu a patient in need thereof . matoid arthritis , osteoarthritis , gouty arthritis and other 92 . The method according to claim 26 , wherein the arthritic conditions ; method comprises more than one administration of cells , ( iii ) the inflammation of the eye is selected from uveitis , and optionally , (i ) the frequency of administrations ranges conjunctivitis , scleritis , keratoconjunctivitis sicca , and from about every other week to about every six months or retinal diseases ; ( ii ) the initial administration is a higher number of cells than ( iv ) the inflammation of the bowels is selected from a subsequent administration . Crohn ' s disease , ulcerative colitis and distal proctitis ; 93 . The method according to claim 26 , wherein the one or ( v ) the inflammation of the skin is selected from psoriasis , more small molecules ( i ) are selected from the group con eczema and dermatitis , scleroderma, ulcers and ero sisting of a glucocorticoid , a prostaglandin pathway agonist , sions resulting from trauma, burns, bullous disorders, an antineoplastic , a dopamine receptor agonist , isomethep or ischemia of the skin or mucous membranes , several tene mucate , dihydrostreptomycin sulfate , protriptyline , forms of ichthyoses, epidermolysis bullosae , hypertro telenzepine , cyclobenzaprine , 4 -aminosalicylic acid , and phic scars, keloids, cutaneous changes of intrinsic combinations thereof; or ( ii ) comprise a prostaglandin path aging, photoaging , frictional blistering caused by way agonist and a glucocorticoid . US 2018 /0112180 A1 Apr. 26 , 2018

94 . The method according to claim 93 , wherein drate , fluocinolone, fluocinolone acetonide , fluocinon ( i) the prostaglandin pathway agonist is selected from ide , fluocortin , fluocoritin butyl, fluocortolone , fluoro PGE2, dmPGE2 , 15 ( S ) - 15 -methyl PGE2, 20 -ethyl cortisone , fluorometholone , fluperolone , fluprednidene, PGE2, 8 - iso - 16 -cyclohexyl - tetranor PGE2, 16 , 16 - dim fluprednidene acetate , fluprednisolone , fluticasone , flu ethyl PGE2 (16 , 16 -dmPGE2 ), p -( p -acetamidoben ticasone propionate , formocortal , halcinonide , halo zamido ) phenyl ester, 11 - deoxy - 16 , 16 -dimethyl PGE , , metasone , hydrocortisone , hydrocortisone acetate , 9 - deoxy - 9 -methylene - 16 , 16 - dimethyl PGE , , 9 - deoxy hydrocortisone aceponate , hydrocortisone buteprate , 9 -methylene PGE2, 9 -keto Fluprostenol, 5 - trans PGE2, hydrocortisone butyrate , loteprednol, meprednisone , 17 - phenyl- omega -trinor PGE2, PGE2 serinol amide , 6a -methylprednisolone , methylprednisolone , methyl PGE2 methyl ester , 16 -phenyl tetranor PGE2, 15 (S ) prednisolone acetate , methylprednisolone aceponate , 15 -methyl PGE2, 15 ( R ) - 15 -methyl PGE2, 8 -iso - 15 mometasone , mometasone furoate , mometasone keto PGE2, 8 - iso PGE , isopropyl ester, 8 - iso - 16 - cyclo furoate monohydrate , paramethasone, prednicarbate , hexyl- tetranor PGE2, 20 - hydroxy PGE2, 20 - ethyl prednisolone , prednisone, prednylidene , rimexolone , PGE2 , 11 -deoxy PGE , nocloprost , sulprostone , tixocortol, triamcinolone, triamcinolone acetonide , ulo butaprost, 15 -keto PGE2, and 19 ( R ) hydroxy PGE2 ; or betasol, and combinations thereof; or ( ii) betametha (ii ) the glucocorticoid is selected from (i ) medrysone , sone, clobetasol proprionate , flumethasone, flucinolone alclometasone , alclometasone dipropionate , amcinon acetonide , medrysone, hydrocortisone , triamcinolone, ide , beclometasone, beclomethasone dipropionate , alclometasone , and dexamethasone . betamethasone , betamethasone benzoate, betametha 95 . The method according to claim 94 , wherein the sone valerate, budesonide , ciclesonide , clobetasol, clo prostaglandin pathway agonist is 16 , 16 - dmPGE2 or PGE2 , betasol butyrate , clobetasol propionate , clobetasone , and the glucocorticoid is dexamethasone. clocortolone , cloprednol, cortisol, cortisone , cortivazol, 96 . The method according to claim 91 , wherein the deflazacort , desonide , desoximetasone , desoxycortone , method comprises more than one administration of cells , desoxymethasone , dexamethasone , diflorasone , and optionally , (i ) the frequency of administrations ranges diflorasone diacetate , diflucortolone, diflucortolone from about every other week to about every six months or valerate , difluorocortolone, difluprednate , fluclorolone , ( ii ) the initial administration is a higher number of cells than fluclorolone acetonide , fludroxycortide, flumethasone , a subsequent administration . flumethasone pivalate , flunisolide , flunisolide hemihy * * * * *