DOCSLIB.ORG

Cd79b Expression in B Cell Chronic Lymphocytic Leukemia: Its Implication for Minimal Residual Disease Detection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cd79b Expression in B Cell Chronic Lymphocytic Leukemia: Its Implication for Minimal Residual Disease Detection Leukemia (1999) 13, 1501–1505 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu CD79b expression in B cell chronic lymphocytic leukemia: its implication for minimal residual disease detection JA Garcia Vela, I Delgado, L Benito, MC Monteserin, L Garcia Alonso, N Somolinos, MA Andreu and F On˜a Department of Hematology, Hospital Universitario de Getafe, Madrid, Spain The surface expression of CD79b, using the monoclonal anti- antigen expression and antigen overexpression) in order to body (Mab) CB3–1, on B lymphocytes from normal individuals establish the applicability of immunophenotypic aberrances and patients with B cell chronic lymphocytic leukemia (CLL) for monitoring MRD as in acute leukemias with a sensitivity has been analyzed using triple-staining cells for flow cytome- −4 try. In addition, the clinical significance of CD79b expression level of 10 (one aberrant CLL cell among 10000 normal in CLL patients and its possible value for the evaluation of mini- cells). We have previously published that CD5 is overex- mal residual disease (MRD) was explored. A total of 15 periph- pressed in most CLL cases.2 This aberrantly CD5high/CD19+ eral blood (PB) samples from healthy blood donors, five bone expression was present in 90% of our CLL. Dilutional experi- marrow (BM) samples from normal donors and 40 PB samples ments showed that CD5high/CD19+ were identified at fre- from CLL untreated patients were included in the study. In −4 addition we studied the expression of CD79b in B lymphocytes quencies as low as 10 . from five CLL patients after fludarabine treatment in order to Recently, different groups have communicated that CD79b support our method. The expression of CD79b in B lympho- (B cell receptor (BCR), B29 protein) is undetectable in the sur- cytes from PB was analyzed by flow cytometry, using simul- face of most CLL cells.5,6 This aberrant phenotype (all CD19+ taneous staining with the Mabs CD22, CD79b, CD19 and CD5, mature lymphocytes express CD79b) has not been studied for CD79b and CD19. Since normal immature bone marrow B cells monitoring MRD in CLL. The aim of our group was to study are CD79b−/dim+ on their surface, in BM samples we used the combination CD45, CD79b and CD19 selecting mature B lym- the expression of CD79b in CLL, to estimate quantitatively the phocytes according to their bright CD45 intensity. Cell acqui- number of molecules per cell, and finally to explore if this sition was performed in two consecutive steps using a live gate antigen could be used in the detection of MRD by flow cyto- drawn on SSC/CD19+ cells. For data analysis, the PAINT-A- metry after treatment. GATE PRO software (Becton Dickinson) was used. Dilution experiments of CD79b− CLL cells and CD79bdim+ CLL cells with normal PB and BM cells were performed in order to assess the sensitivity level of the technique for detection of CD79b−/dim+ Materials and methods residual CLL cells. All B lymphocytes from normal samples showed reactivity for the CD79b antigen. In contrast, CD79b was absent in 18/40 CLL patients (42.5%) and 20/40 CLL cases Patients and samples (50%) exhibited a low CD79b expression. Therefore, CD79b− B lymphocytes would be restricted to the CLL population and A total of 20 healthy donors: 15 peripheral blood (PB) samples thus could be considered a ‘tumor phenotype’ for monitoring MRD in CLL patients. Dilution experiments indicate that the and five bone marrow (BM) samples and 40 PB samples from detection limit with this marker almost reaches the levels untreated CLL patients were included in the present study. PB obtained by molecular biology methods as the PCR technique. and BM aspirates were available for review in all patients, All cases studied after fludarabine presented leukemic cells in bone marrow trephines in 33 patients and lymph node aspir- their PB or BM samples detected by flow cytometry. Upon com- ates or biopsies in 13 cases. All slides were reviewed and paring the clinical and morphological characteristics of CD79b− + classified according to both the REAL classification and the and CD79b cases, all atypical CLL cases included in the 7,8 present study were CD79b+ and advanced clinical stage (B and FAB cooperative group criteria. The diagnosis of CLL was C Binet stage) was most frequently observed in CD79b+ cases confirmed by immunophenotype using a large panel of mono- than in CD79b− cases. clonal antibodies (Mabs) with a direct immunofluorescence Keywords: CD79b; CLL; minimal residual disease; immunopheno- technique: FMC7, CD5, CD10, CD11c, CD19, CD20, CD22, type CD23, CD25, CD43, CD103 and polyclonal anti-␬ and anti- ␭ surface light chains (slg) to determinate B cell clonal excess. A typical CLL immunophenotype was defined as CD5+/ Introduction CD23+/CD19+/CD22−/dim+/CD20dim+/CD10−/CD103−/FMC7−/dim+ and slgdim. CLL was further subdivided into typical and atypi- It has been shown that immunophenotypic analysis is a useful cal CLL on morphology without considering the immuno- approach for the investigation of minimal residual disease phenotype.9 Atypical CLL included cases with more than 10% (MRD) in acute leukemia patients.1 At present this approach circulating prolymphocytes (CLL/PL) and others with more has not been used in B cell chronic lymphocytic leukemia than 15% lymphocytes with lymphoplasmacytic features (CLL) for MRD detection, with the exception of the and/or cleaved nuclei. According to the REAL classification kappa/lambda ratio but the sensitivity of this parameter is low and FAB criteria, all cases included were classified as CLL. (10−2).1 We and others2–4 have explored the incidence of There were no cases with mantle zone lymphoma, follicle phenotypic aberrances in CLL (maturational asynchronous center cell lymphoma, lymphoplasmacytoid lymphoma and splenic marginal zone B cell lymphoma. Six out of 40 CLL cases displayed atypical lymphocyte morphology in the blood film. Correspondence: JA Garcia Vela, Department of Hematology, Hospi- tal Universitario de Getafe, Carretera de Toledo KM 12,500, Getafe The mean age of normal blood donors (eight males, seven 28905, Madrid, Spain; Fax: 34 91 6833541 females) was 49.5 ± 12.9 years and 68.2 ± 11.3 for CLL Received 7 July 1998; accepted 25 May 1999 patients. According to the Binet clinical staging classi- CD79b expression in CLL JA Garcia Vela et al 1502 fication,10 CLL patients were distributed as follows: A 67.5%, San Juan, PR). Each marker was considered to be positive B 17.5% and C 15%. when the mean MESF obtained was at least double that Five patients were studied prior to treatment and at the time observed in the isotype-negative control tube. of maximal response after fludarabine treatment which was defined as: CR, nodular PR (nPR) or PR. Criteria for CR were normal physical examination, absence of constitutional symp- Dilution experiments toms, PB lymphocyte count Ͻ4 × 109/l, platelets Ͼ100 × 109/l, Hb Ͼ11 g/dl and Ͻ30% lymphoid cells in the BM aspirate Dilution experiments were performed in order to assess the with normal histology. The presence of residual nodular or sensitivity level of this technique for the detection of interstitial lymphoid aggregates in the BM was considered as CD79b−/dim+/CD19+ leukemic cells. For this purpose, progress- nPR. The presence of more than 30% lymphocytes in the BM ive dilutions of a CLL sample with normal PB and BM were aspirate after normalization of all other parameters was carried out at ratios of up to one CLL cell in 106 normal cells defined as PR. prior to staining with Mabs as previously described. Five ml of EDTA-anticoagulated PB or BM samples were obtained in all cases after informed consent according to the Hospital Ethical Committee. Statistical analysis The Mann–Whitney test was used to compare the MESF value Immunophenotypical studies of CD79b among the two groups, CLL and normal donors, and to demonstrate the correlation between the expression of In all cases unseparated PB samples (1–2 × 106/tube) were CD79b and the other markers analyzed in the present study. stained with a simultaneous triple labeling using the Mabs CD5 and CD22 conjugated with fluorescein isothiocyanate (FITC), CD79b conjugated with phycoerythrin (PE) and CD19 Results conjugated with the PE/Cyanin5 fluorochrome tandem (Tricolor). Since normal immature BM B cells are CD79b−/dim+ The mean frequency of B lymphocytes CD19+ in the normal as CLL cells, in all BM samples we used the combination PB samples analyzed was 8.4 ± 4.0% (range: 4.3–14%) of CD19-FITC/CD79b-PE/CD45-PerCP. Immature B cells lymphocytes, whereas in CLL PB samples it was (CD45−/dim+) were separate from mature B lymphocytes 74.09 ± 16.68% (range: 34–98%). The overall proportion of (CD45bright) according to the different CD45 expression.11 The CD19+ cells in the normal BM samples was 3.14 ± 1.68% CD5, CD19, CD22 and CD45 Mabs were purchased from (range: 0.7–6.4%) and 70.8 ± 14.3% of them showed a bright Becton Dickinson (San Jose´, CA, USA), CD79b (CB3-1) from expression of CD45. In normal PB, B lymphocytes expressing Immunotech (Marseille, France) and CD19-PE/Cy5 from Cal- CD5 represented 2.5 ± 1.4% of lymphocytes (MESF tag Laboratories (San Francisco, CA, USA). Samples were 6.6 ± 0.4 × 103). In the CLL group, all cases were CD5+ and it incubated for 15 min at room temperature in the dark with was expressed in practically all CD19+ cells (MESF saturating amounts of the fluorochrome-conjugated Mab 78.4 ± 43.1 × 103); 24 out of 40 cases (60%) showed a weak reagents. Afterwards, 2 ml of FACS lysing solution (Becton expression of CD22 (MESF 7.5 ± 2.8 × 103).
Load more

Recommended publications
  • Molecules with Specificity for Cd45 and Cd79 Moleküle Mit Cd45- Und Cd79-Spezifizität Molécules Présentant Une Spécificité Vis-À-Vis De Cd45 Et Cd79
    (19) *EP003169704B1* (11) EP 3 169 704 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 16/28 (2006.01) 29.07.2020 Bulletin 2020/31 (86) International application number: (21) Application number: 15738655.8 PCT/EP2015/066368 (22) Date of filing: 16.07.2015 (87) International publication number: WO 2016/009029 (21.01.2016 Gazette 2016/03) (54) MOLECULES WITH SPECIFICITY FOR CD45 AND CD79 MOLEKÜLE MIT CD45- UND CD79-SPEZIFIZITÄT MOLÉCULES PRÉSENTANT UNE SPÉCIFICITÉ VIS-À-VIS DE CD45 ET CD79 (84) Designated Contracting States: • WRIGHT, Michael John AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Slough GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Berkshire SL1 3WE (GB) PL PT RO RS SE SI SK SM TR • TYSON, Kerry Designated Extension States: Slough BA ME Berkshire SL1 3WE (GB) Designated Validation States: MA (74) Representative: UCB Intellectual Property c/o UCB Celltech (30) Priority: 16.07.2014 GB 201412659 IP Department 208 Bath Road (43) Date of publication of application: Slough, Berkshire SL1 3WE (GB) 24.05.2017 Bulletin 2017/21 (56) References cited: (73) Proprietor: UCB Biopharma SRL WO-A1-2011/025904 WO-A1-2013/085893 1070 Brussels (BE) • GOLD ET AL.: "The B Cell Antigen Receptor (72) Inventors: Activates the AKT/Glycogegn Synthase Kinase-3 • FINNEY, Helene Margaret Signalling Pathway via Phosphatydilinositol Slough 3-Kinase", J. IMMUNOLOGY, vol. 163, 1999, Berkshire SL1 3WE (GB) pages 1894-1905, XP002745175, • RAPECKI, Stephen Edward Slough Berkshire SL1 3WE (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • ORIGINAL ARTICLE Flow Cytometric Protein Expression Profiling As a Systematic Approach for Developing Disease-Specific Assays
    Leukemia (2006) 20, 2102–2110 & 2006 Nature Publishing Group All rights reserved 0887-6924/06 $30.00 www.nature.com/leu ORIGINAL ARTICLE Flow cytometric protein expression profiling as a systematic approach for developing disease-specific assays: identification of a chronic lymphocytic leukaemia-specific assay for use in rituximab-containing regimens AC Rawstron, R de Tute, AS Jack and P Hillmen Haematological Malignancy Diagnostic Service (HMDS), Leeds Teaching Hospitals, Leeds, UK Depletion of disease below the levels detected by sensitive sustained remissions only occur in patients achieving an MRD- minimal residual disease (MRD) assays is associated with negative complete response.12 Therefore MRD is increasingly prolonged survival in chronic lymphocytic leukaemia (CLL). being used as an end point for therapeutic trials, and several Flow cytometric MRD assays are now sufficiently sensitive and rapid to guide the duration of therapy in CLL, but generally rely studies are now using the assessment of MRD to define the on assessment of CD20 expression, which cannot be accurately duration of therapy. measured during and after therapeutic approaches containing Approaches using allele-specific oligonucleotide polymerase rituximab. The aim of this study was to use analytical software chain reaction (ASO-PCR) to the immunoglobulin gene of the developed for microarray analysis to provide a systematic B-CLL cell are generally accepted to show the highest sensitivity approach for MRD flow assay development. Samples from CLL for MRD detection. However, more recent four-colour ap- patients (n ¼ 49), normal controls (n ¼ 21) and other B-lympho- proaches show sensitivities nearing that of ASO-PCR6,11,13 with proliferative disorders (n ¼ 12) were assessed with a panel of 66 antibodies.
    [Show full text]
  • ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor–BTK Signaling Pathway † Qian Zhang,* Hong Y
    Published September 18, 2019, doi:10.4049/jimmunol.1801327 Cutting Edge: ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor–BTK Signaling Pathway † Qian Zhang,* Hong Y. Wang,* Xiaobin Liu,* Selene Nunez-Cruz,* Mowafaqx Jillab, Olga Melnikov,† Kavindra Nath,‡ Jerry Glickson,‡ and Mariusz A. Wasik*,†, Inhibitors of Bruton tyrosine kinase (BTK), a kinase these mechanisms is of uttermost importance in design- downstream of BCR, display remarkable activity in a ing an appropriate therapeutic strategy to counteract the subset of mantle cell lymphoma (MCL) patients, but reprogramming. the drug resistance remains a considerable challenge. In ROR1 belongs to the receptor tyrosine kinase-like orphan this study, we demonstrate that aberrant expression of receptor (ROR) family and displays very restricted expression ROR1 (receptor tyrosine kinase-like orphan receptor 1), in normal tissues (11, 12). ROR1 is aberrantly expressed in seen in a large subset of MCL, results in BCR/BTK– various malignancies, including small lymphocytic lymphoma/ independent signaling and growth of MCL cells. ROR1 chronic lymphocytic leukemia (SLL/CLL) and MCL. ROR1 forms a functional complex with CD19 to persistently activates signaling molecules, such as RAC-1 and contractin activate the key cell signaling pathways PI3K–AKT and (13, 14), to promote cell proliferation, survival, and migration MEK–ERK in the BCR/BTK–independent manner. (13–15). CD19 is a B cell–specific receptor capable of stimu- lating the growth of malignant B cells (16). In normal This study demonstrates that ROR1/CD19 complex B lymphocytes, it is activated by SRC family kinases and effectively substitutes for BCR–BTK signaling to SYK, both downstream of BCR (17).
    [Show full text]
  • B Cell Checkpoints in Autoimmune Rheumatic Diseases
    REVIEWS B cell checkpoints in autoimmune rheumatic diseases Samuel J. S. Rubin1,2,3, Michelle S. Bloom1,2,3 and William H. Robinson1,2,3* Abstract | B cells have important functions in the pathogenesis of autoimmune diseases, including autoimmune rheumatic diseases. In addition to producing autoantibodies, B cells contribute to autoimmunity by serving as professional antigen- presenting cells (APCs), producing cytokines, and through additional mechanisms. B cell activation and effector functions are regulated by immune checkpoints, including both activating and inhibitory checkpoint receptors that contribute to the regulation of B cell tolerance, activation, antigen presentation, T cell help, class switching, antibody production and cytokine production. The various activating checkpoint receptors include B cell activating receptors that engage with cognate receptors on T cells or other cells, as well as Toll-like receptors that can provide dual stimulation to B cells via co- engagement with the B cell receptor. Furthermore, various inhibitory checkpoint receptors, including B cell inhibitory receptors, have important functions in regulating B cell development, activation and effector functions. Therapeutically targeting B cell checkpoints represents a promising strategy for the treatment of a variety of autoimmune rheumatic diseases. Antibody- dependent B cells are multifunctional lymphocytes that contribute that serve as precursors to and thereby give rise to acti- cell- mediated cytotoxicity to the pathogenesis of autoimmune diseases
    [Show full text]
  • Molecular Design, Optimization and Genomic Integration of Chimeric B
    bioRxiv preprint doi: https://doi.org/10.1101/516369; this version posted June 5, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Molecular design, optimization and genomic integration of chimeric B cell 2 receptors in murine B cells 3 4 Theresa Pesch1, Lucia Bonati1, William Kelton1, Cristina Parola1,2, Roy A Ehling1, Lucia 5 Csepregi1, Daisuke Kitamura3, Sai T ReDDy1,* 6 7 1 Department of Biosystems Science and Engineering, ETH Zürich, Basel 4058, Switzerland 8 2 Life Science Graduate School, Systems Biology, ETH Zürich, University of Zurich, Zurich 8057, 9 Switzerland 10 3 Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan 11 *To whom corresponDence shoulD be aDDresseD. Tel: +41 61 387 33 68; Email: [email protected] 12 Key worDs: B cells, synthetic antigen receptor, cellular engineering, genome eDiting, cellular 13 immunotherapy, CRISPR-Cas9 14 15 Abstract 16 Immune cell therapies baseD on the integration of synthetic antigen receptors proviDe 17 a powerful strategy for the treatment of Diverse Diseases, most notably retargeting 18 T cells engineereD to express chimeric antigen receptors (CAR) for cancer therapy. In 19 aDDition to T lymphocytes, B lymphocytes may also represent valuable immune cells 20 that can be engineereD for therapeutic purposes such as protein replacement therapy 21 or recombinant antiboDy proDuction. In this article, we report a promising concept for 22 the molecular Design, optimization anD genomic integration of a novel class of 23 synthetic antigen receptors, chimeric B cell receptors (CBCR).
    [Show full text]
  • Downloaded and Further Processed with the R Programming Language ( and Bioconductor ( Software
    bioRxiv preprint doi: https://doi.org/10.1101/801530; this version posted October 13, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. An integrated multi-omic single cell atlas to redefine human B cell memory David R. Glass,1,2,5 Albert G. Tsai,2,5 John Paul Oliveria,2,3 Felix J. Hartmann,2 Samuel C. Kimmey,2,4 Ariel A. Calderon,1,2 Luciene Borges,2 Sean C. Bendall1,2,6,* 1Immunology Graduate Program, Stanford University, Stanford, CA, 94305, USA 2Department of Pathology, Stanford University, Stanford, CA, 94305, USA 3Department of Medicine, Division of Respirology, McMaster University, Hamilton, ON, L8S4K1, Canada 4Department of Developmental Biology, Stanford, University, Stanford CA, 94305, USA 5Co-first author 6Lead Author *Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/801530; this version posted October 13, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Abstract: To evaluate the impact of heterogeneous B cells in health and disease, comprehensive profiling is needed at a single cell resolution. We developed a highly- multiplexed screen to quantify the co-expression of 351 surface molecules on low numbers of primary cells. We identified dozens of differentially expressed molecules and aligned their variance with B cell isotype usage, metabolism, biosynthesis activity, and signaling response.
    [Show full text]
  • Immunotherapies Shape the Treatment Landscape for Hematologic Malignancies Jane De Lartigue, Phd
    Feature Immunotherapies shape the treatment landscape for hematologic malignancies Jane de Lartigue, PhD he treatment landscape for hematologic of TIL therapy has been predominantly limited to malignancies is evolving faster than ever melanoma.1,3,4 before, with a range of available therapeutic Most recently, there has been a substantial buzz Toptions that is now almost as diverse as this group around the idea of genetically engineering T cells of tumors. Immunotherapy in particular is front and before they are reintroduced into the patient, to center in the battle to control these diseases. Here, increase their anti-tumor efficacy and minimize we describe the latest promising developments. damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the Exploiting T cells T-cell receptor to alter its specificity (TCR T cells) The treatment landscape for hematologic malig- or by generating artificial fusion receptors known as nancies is diverse, but one particular type of therapy chimeric antigen receptors (CAR T cells; Figure 1). has led the charge in improving patient outcomes. The former is limited by the need for the TCR to be Several features of hematologic malignancies may genetically matched to the patient’s immune type, make them particularly amenable to immunother- whereas the latter is more flexible in this regard and apy, including the fact that they are derived from has proved most successful. corrupt immune cells and come into constant con- CARs are formed by fusing part of the single- tact with other immune cells within the hemato- chain variable fragment of a monoclonal antibody poietic environment in which they reside.
    [Show full text]
  • New Additions to Antibody Panels in the Characterisation of Chronic Lymphoproliferative Disorders J Clin Pathol: First Published As on 1 March 2002
    180 REVIEW New additions to antibody panels in the characterisation of chronic lymphoproliferative disorders J Clin Pathol: first published as on 1 March 2002. Downloaded from E Matutes ............................................................................................................................. J Clin Pathol 2002;55:180–183 Advances in flow cytometry techniques and the In addition to the panel of monoclonal antibod- availability of monoclonal antibodies that detect key ies routinely used in the past decade,2 and recom- mended in 1994 by the general haematology task functional molecules on lymphocytes have contributed force of the British Committee for Standards in greatly to a more precise diagnosis of the chronic Haematology,3 several others have been shown to lymphoproliferative disorders. In addition to the provide relevant diagnostic and/or prognostic information, and could be incorporated into the diagnostic value, the expression of certain markers such panel of markers in a routine practice. The as p53 or CD38 provides relevant prognostic characteristics of these monoclonal antibodies information to the clinician. Beyond their diagnostic and and the molecules that they recognise, in addition to their relevance for the characterisation of the prognostic value, immunological markers play a major chronic lymphoproliferative disorders, are de- role in the detection of minimal residual disease, scribed below enabling the clinician to estimate more accurately the response to chemotherapy. Those monoclonal MONOCLONAL ANTIBODIES TO CD79B CD79 is a heterodimeric molecule comprising two antibodies that are relevant to the characterisation of the polypeptide chains: the α-chain or mb1 (CD79a) chronic lymphoproliferative disorders and that could be and the β-chain or B29 (CD79b). CD79b is incorporated in a routine practice are discussed.
    [Show full text]
  • B-Cell Development, Activation, and Differentiation
    B-Cell Development, Activation, and Differentiation Sarah Holstein, MD, PhD Nov 13, 2014 Lymphoid tissues • Primary – Bone marrow – Thymus • Secondary – Lymph nodes – Spleen – Tonsils – Lymphoid tissue within GI and respiratory tracts Overview of B cell development • B cells are generated in the bone marrow • Takes 1-2 weeks to develop from hematopoietic stem cells to mature B cells • Sequence of expression of cell surface receptor and adhesion molecules which allows for differentiation of B cells, proliferation at various stages, and movement within the bone marrow microenvironment • Immature B cell leaves the bone marrow and undergoes further differentiation • Immune system must create a repertoire of receptors capable of recognizing a large array of antigens while at the same time eliminating self-reactive B cells Overview of B cell development • Early B cell development constitutes the steps that lead to B cell commitment and expression of surface immunoglobulin, production of mature B cells • Mature B cells leave the bone marrow and migrate to secondary lymphoid tissues • B cells then interact with exogenous antigen and/or T helper cells = antigen- dependent phase Overview of B cells Hematopoiesis • Hematopoietic stem cells (HSCs) source of all blood cells • Blood-forming cells first found in the yolk sac (primarily primitive rbc production) • HSCs arise in distal aorta ~3-4 weeks • HSCs migrate to the liver (primary site of hematopoiesis after 6 wks gestation) • Bone marrow hematopoiesis starts ~5 months of gestation Role of bone
    [Show full text]
  • Novel Immunotherapies in Lymphoid Malignancies
    REVIEWS Novel immunotherapies in lymphoid malignancies Connie Lee Batlevi1, Eri Matsuki1, Renier J. Brentjens2 and Anas Younes1 Abstract | The success of the anti‑CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T‑cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T‑cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome- negative relapsed and/or refractory B‑precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD‑1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. The concept of immunotherapy for treating cancer of cell-based therapy directed at TAAs expressed on the emerged almost a century ago; the graft-versus-tumour tumour-cell surface, typically CD19 in B‑cell malignan- effect following allogeneic haematopoietic-stem-cell cies (BOX 1).
    [Show full text]
  • Chimeric Antigen Receptor T Cells Targeting Cd79b Show Efficacy in Lymphoma with Or Without Cotargeting CD19
    Published OnlineFirst August 22, 2019; DOI: 10.1158/1078-0432.CCR-19-1337 Precision Medicine and Imaging Clinical Cancer Research Chimeric Antigen Receptor T Cells Targeting CD79b Show Efficacy in Lymphoma with or without Cotargeting CD19 Maria Ormhøj1,2, Irene Scarfo1, Maria L. Cabral1, Stefanie R. Bailey1, Selena J. Lorrey1, Amanda A. Bouffard1, Ana P. Castano1, Rebecca C. Larson1, Lauren S. Riley1, Andrea Schmidts1, Bryan D. Choi1, Rikke S. Andersen3, Oriane Cedile 4,6,7, Charlotte G. Nyvold4,6,7, Jacob H. Christensen5, Morten F. Gjerstorff3,8, Henrik J. Ditzel3,8, David M.Weinstock9,10,Torben Barington2,7, Matthew J. Frigault1,10, and Marcela V. Maus1,10 Abstract Purpose: T cells engineered to express a chimeric antigen Results: We demonstrate CAR79b antigen-specificrecog- receptor (CAR) against CD19 have recently been FDA nition and cytotoxicity against a panel of cell lines and approved for the treatment of relapsed or refractory large B- patient-derived xenograft models of MCL. Importantly, we cell lymphoma. Despite the success and curative potential of show that downregulation of CD19 does not influence CD19 CAR T cells, several reports describing disease relapse surface expression of CD79b and that anti-CD79b CAR due to antigen loss are now emerging. T cells alone or arranged in a dual-targeting format with Experimental Design: We developed a novel CAR construct a CD19 single-chain variable fragment (scFv) are able to þ À directed against CD79b, a critical receptor for successful B-cell recognize and eliminate CD19 ,CD19, and mixed þ À development that remains highly expressed in several sub- CD19 /CD19 B-cell lymphoma.
    [Show full text]
  • The Diagnostic Value of CD123 in B-Cell Disorders with Hairy Or Villous Lymphocytes
    Chronic Lymphoproliferative Disorders • Research Paper The diagnostic value of CD123 in B-cell disorders with hairy or villous lymphocytes [haematologica] 2004;89:303-308 ILARIA DEL GIUDICE ABSTRACT ESTELLA MATUTES RICARDO MORILLA Background and Objectives. CD123 is an antibody that identifies the α chain of the ALISON MORILLA human interleukin-3 receptor and is expressed in a variety of normal hematopoietic cells, KWASI OWUSU-ANKOMAH acute leukemia and hairy cell leukemia (HCL). The aim of the study was to investigate the FURHEEN RAFIQ diagnostic value of CD123 expression in B-cell disorders with circulating hairy and vil- ROGER A’HERN lous lymphocytes. JULIO DELGADO Design and Methods. We investigated the diagnostic value of CD123 expression in neo- MOHAMMED BADIE BAZERBASHI plastic cells from 59 patients with B-cell disorders with circulating hairy or villous lym- DANIEL CATOVSKY phocytes: HCL (n=24), the variant form of HCL (n=11) and splenic lymphoma with villous lymphocytes (SLVL) (n=24). Cells from 12 patients with chronic lymphocytic leukemia were used as controls. Immunophenotypic analysis was performed by flow cytometry on 77 samples from peripheral blood (n=48), bone marrow (n=25) and spleen cell suspensions (n=4). Results. Our findings show that cells from 95% of typical HCL express CD123 with strong to moderate intensity while this molecule is absent in circulating cells from most cases of HCL-variant (91%) and SLVL (97%). Interpretation and Conclusions. We conclude that CD123 is a useful new marker for distinguishing B-cell disorders with circulating villous lymphocytes as its expression is characteristic of typical HCL with high sensitivity and specificity.
    [Show full text]