CROHNS’S DISEASE

NORMAL COLON

HUMIRA Adalimumab AbbVie, Inc. Infliximab Johnson & Johnson blocks TNF (psoriasis, Crohns disease, etc. HUMIRA CROHN DISEASE

PHYSICIANS GLOBAL ASSESSMENT: STOOL FREQUENCY, RECTAL BLEEDING, ENDOSCOPY ENTYVIO

Vedolizumab Millennium Pharmaceuticals, Binds to and blocks α₄β₇ integrin - gut-selective anti-inflammatory activity. α₄β₇ integrin on T-cells binds to mucosal addressin MadCAM1, VCAM-1 and Fironectin. Critical for T-cell homing to intestinal mucosa and activation of T-cells

Critical in T-cell trafficking in intestinal graft vs. host disease and Crhon’s disease ENTYVIO - CROHN’S DISEASE

STELARA PSORIASIS PERCENTAGE OF PATIENT’S WITH VISIBLE DECREASE IN LESIONS

PLAQUE PSORIASIS

PSORITIC ARTHRITIS STALARA (ANTI IL-12,23) CROHN’S DISEASE BLOCK PROGRESSION OF DISEASE

POLYMYOSITIS AND INTERSTITIAL BODY MYOSITIS NORMAL MUSCLE POLYMYOSITIS MYOSITIS ASSOCIATED ANTIBODIES MYOSITIS RONTALIZUMAB, SIFALMUMAB INF-α INFLIXIMAB Il-10 TOCILIZUMAB IL-6R RITUXIMAB, ETC. CD20 EPRATUZMAB CD22 CANCER ASSOCIATED MYOSITIS

Transcription intermediary factor 1-gamma (TIF1-γ), TUMOR IMMUNITY T-CTL

Check point inhibitors

CAR-T-cells

COMING OSHER ATTRACTION

TUMOR IMMUNITY APRIL 14, 2021 ANTI-CTLA-4 THERAPY CTLA4 blocks tumor immunity (CHECK POINT REGULATOR) Reversal by treatment with anti-CTLA-4 antibody. IPILIMUMAB

a. Specific T-cells are activated by tumor specific antigen peptides X presented by dendritic cells to the TCR and through co-stimulation Through B7 and CD28

b. CTLA 4 is then upregulated, displaces CD28 and attenuates the T-cell response.

c. Treatment with anti-CTLA-4 blocks CTLA4 activity and allows re-establishment of T-cell activation

d. Activated T-cells can now effect tumor cell death.

I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673 CHECK POINT INHIBITOR THERAPY ANTI-CTLA4 AND ANTI-PD1 KEYTRUDA NON-SMALL CELL LUNG CANCER

Selected Safety information: Pneumonitis (12); Colitis (4); Hepatitis (2); Hypophysitis (2); Nephritis (3); Hyperthyroidism (5); dermatitis; uveitis; arthritis myositis; pancreatitis; seizures; adrenal insufficiency; myasthenia syndrome; optic neuritis; and rhabdomyolysis (Less than 1%). Discontinued 1n 9% of patients. From The New England Journal of Medicine, Reck M, Rodríguez-Abreu D, et al, for the KEYNOTE- 024 Investigators, Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer, 2016 Oct 8. [Epub ahead of print]. doi:10.1056/NEJMoa1606774. Accessed 25 October 2016. Copyright © 2016 Massachusetts Medical Society. CANCER ANTIGEN RECEPTOR CAR CLINICAL TRIALS Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized the care of patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Results from clinical trials across multiple institutions report remarkable remission rates with CD19-directed CAR-modified T-cell therapy. These remissions are also proving to be durable in many patients with a relapse-free survival (RFS) of approximately 50% to 60% at 1 year across several trials and institutions in this population that has been historically very difficult to treat..

DiNoffa AM, et al. Chimeric antigen receptor T-cell therapy clinical trial: Results in pediatric and young adult B-cell ALL. HemaSphere. 3:279, 2019 T-CELL CYTOXICITY CONTACT DERMATITIS SMALL POX MEASLES INFLUENZA GRAFT VS. HOST GRAFT REJECTION PSORIASIS ALOPECIA CHRONIC HEPATITIS CROHN DISEASE POLYMYOSITIS TUMOR IMMUNITY

MONOCLONAL ANTIBODY TREATMENTS DELAYED HYPERSENSITIVITY

SKIN REACTION MOSQUITO BITE CHIGGER BITE SYPHILIS DEMYELINATING DISEASES DELAYED HYPERSENSITVITY DELAYED HYPERSENSITIVTY BARRYBARRY BILLBILL CHARLIECHARLIE PAULPAUL DELAYEDDELAYED HYPERSENSITIVITYHYPERSENSITIVITY PIERCE WEIGLE COCHRANE MAUER PIERCE WEIGLE COCHRANE MAUER 24 HOURS2424 HOURHOUR SKINSKIN TESTTEST TOTO BGGBGG

BILL WEIGLE UNIVERSITYUNIVERSITY OF OF PITTSBURGH PITTSBURGH 19581958

ARTHUSARTHUS SKINSKIN REACTIONREACTION ARTHUS5 HOUR SKINREACTION TEST TO – AB BGG 55 HOURSHOUR SKIN TEST TO BGG Sell, S. and Weigle, W.O. The relationship between delayed hypersensitivity and circulating antibody induced by protein antigens in guinea pigs. J. Immunol. 83:257-263, 1959.

DTH HISTOLOGY PERIVASCULAR MONONUCLEAR CELL

NERVE

VEIN

ARTERY DTH - TATOO

40 X 200 X

400 X 400 X DTH MOSQUITO BITE VEINULE

MIXTURE OF LYMPHOCYTES EOSINOPHILS AND MACROPHAGES CHIGGER BITE

. Bites may go unnoticed until 1-3 hours later, after the mite secretes a digestive enzyme into the skin which kills skin cells. These dead skin cells form a tube called a stylostome which the larva uses to withdraw digested tissue. It is the presence of this enzyme that is responsible for intense itching. The itching is most intense in the first 24-48 hours then gradually subsides. Chigger dermatitis can present as a red flat or raised lesion. A vesicle or pustule may also be present. Resolution of chigger dermatitis can take up to two weeks to completely resolve SYPHILIS

On the Plague of the Cursed Glands

Francisco Lopez de Villalobos

1473-1529

French translation 1890

Original Latin 1498 SYPHILIS Oueen Isabella 1496

Columbus

Syphilis

Ruy Diaz de Isla The Serpentine Disease 1539

SYPHILIS PRIMARY CHANCRE

On the Plague of the Cursed Glands Francisco Lopez de Villalobos 1473-1529 French translation 1890 Original Latin 1498 SECONDARY SYPHILIS SMALL POX GREAT POX

SYPHILIS PRIMARY CHANCRE OF SYPHILIS HUMAN RABBIT

•Carlson JA, Dabri G, Cribier B, Sell S. The immunopathobiology of syphilis. The manifestations and course •of syphilis are determined by the level of delayed hypersensitivity. Am. J. Dermatopathol. 33:433–460, 2011. • JAMES MILLER UCLA

SHEILA LUKEHART STEVE NORRIS U. WASHINGTON U. TEXAS, HOUSTON EXPERIMENTAL SYPHILIS IN RABBIT SKIN

EXPERIMENTAL SYPHILIS IN RABBIT TESTIS

DAY 3 DAY 10

DAY 13 DAY 17 FLOURESCENT FRAGMENTS IN MACROPHAGES DAY 14

Lukehart, S.A., Baker-Zander, S.A., Lloyd, R.M. and Sell, S. Characterization of lymphocyte responsiveness in early experimental syphilis II. Nature of cellular infiltration and Treponema pallidum distribution in testicular lesions. J. Immunol. 14:461-467, 1979. PHAGOCYTOSIS AND DIGESTION OF T. PALLIDUM

Sell, S., Baker-Zander, S., and Powell H.C. Experimental syphilic orchitis in rabbits. Ultrastructural appearance of T. pallidum during phagocytosis and dissolution by macrophges in vivo. Lab. Invest. 46:355-364, 1982.

EAE IS A MODEL FOR POST-VACCINIAL ENCEPHALOMYELITIS POST VACCINIAL DEMYLINATION EAE LYMPH ENTERING BRAIN

EAE MACROPHAGE STRIPPING AND PHAGOCYTOSING MYELIN

Fibrinoid necrosis

Palisading histiocytes

Connective tissue With lymphocytes and plasma cells RHEUMATOID NODLUE GRANULOMAS IN LUNG TUBERCULOSIS LANGHAN’S GIANT CELL FOREIGN BODY GIANT CELL LANGHAN’S GIANT CELL

ACID FAST MYCOBACTERIUM

SARCOIDOSIS SILICOSIS

CRYSTILLINE SILICA DUST DEPOSITED IN THE LUNGS PHAGOCYTOSED BY MACROPHAGES INCITES INFLAMMATION - TNF, IL-1, LEUKOTRINES AND CYTOKINES

FIBROTIC NODULES, SCARRING, EMPHYSEMA DESTRUCTION OF LUNG TISSUE SARCOID GRANULOMATA UNKNOWN

SARCOIDOSIS Failure to control DTH response CHRONIC BERYLLIOSIS Occupational disease – metals containing beryllium (aerospace, fluorescent light bulbs, microwaves)

Beryllium acts as a hapten; induces DTH with macrophage activation.

Macrophages cannot digest beryllium.

GRANULOMASL

NONCASEATING GRANULOMAS SCHAUMANN BODIES WEGENER’S GRANULOMATOSIS GRANULOMATOSIS WITH POLYANGITIS “AUTOIMMUNE DISEASE OF UNKNOWN ORIGIN” GRANULOMAS, PAUCI- IMMUNE VASCULITIS, AND GLOMERULONEPHRITIS AUTOANTIBODY TO PROTEINASE 3 (PR3-ANCA) ANCA ACTIVATON OF PMNs WHICH REACT WITH ENDOTHELIAL CELLS (VASCULITIS) CD-4+ T-CELLS PLUS MACROPHAGES (Th1) NOT DAMPANED BY Th2 ARM.

Gross WL, Trabandi A, Csermok E. Pathogenesis of Wegerer’s granulomatosis. Ann Med Interne (Paris) 149:280-6, 1998

IMMUNE EFFECTOR MECHANISMS LEVELS OF REACTIONS OF ANTIGEN WITH ANTIBODY OR CELLS

PRIMARY SECONDARY TERTIARY REACTION REACTION REACTION in vitro in vivo ANTIBODY MEDIATED INACTIVATION NEUTRALIZATION

AGGLUTINATION, LYSIS CYTOLYTIC REACTIONS OPSONIZATION Ag+Ab AgAb IMMUNE COMPLEX PRECIPITATION REACTIONS

MAST CELL ANAPHYLACTIC DEGRANULATION REACTIONS

CELL MEDIATED DELAYED T-DTH HYPERSENSITIVITY LYMPHOKINES REACTIONS +Ag-> MACROPHAGE ACTIVATION

BLAST CELL TRANSFORMATION T-CTL TARGET-CELL LYSIS DESTRUCTION

Ab or + INSOLUBLE ANTIGEN GRANULOMA CELL-MEDIATED IMMUNITY

T-CELL CYTOTOXICITY

DELAYED HYPERSENSITIVITY

GRANULOMATOUS REACTIONS