Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion.
B cells play a central role in antibody-mediated rejection and certain autoimmune diseases. However, B cell-targeted therapy such as anti-CD20 B cell-depleting antibody (aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B cell reconstitution leading to aCD20 depletion resistance could account for these discrepancies. Using a transplantation model, we found that antigen-independent inflammation, likely through toll-like receptor (TLR) signaling, was sufficient to mitigate B cell depletion. Secondary lymphoid organs had a quicker recovery of B cells when compared to peripheral blood. Inflammation altered the pharmacokinetics (PK) and pharmacodynamics (PD) of aCD20 therapy by shortening drug half-life and accelerating the reconstitution of the peripheral B cell pool by bone marrow-derived B cell precursors. IVIG (intravenous immunoglobulin) coadministration also shortened aCD20 drug half-life and led to accelerated B cell recovery. Repeated aCD20 dosing restored B cell depletion and delayed allograft rejection, especially B cell-dependent, antibody-independent allograft rejection. These data demonstrate the importance of further clinical studies of the PK/PD of monoclonal antibody treatment in inflammatory conditions. The data also highlight the disconnect between B cell depletion on peripheral blood compared to secondary lymphoid organs, the deleterious effect of IVIG when given with aCD20 and the relevance of redosing of aCD20 for effective B cell depletion in alloimmunity.
Department of Medicine, Oregon Health & Science University, Portland, OR.
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LH
Laws
Department of Medicine, Oregon Health & Science University, Portland, OR.
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CE
Parker
Department of Pharmacy Practice, College of Pharmacy, Oregon State University, Portland, OR.
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Cherala
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR.
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Koguchi
Institute for Molecular Medicine, Johannes Gutenberg University Mainz, Mainz, Germany.
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Waisman
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR.
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Slifka
Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA.
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Oberbarnscheidt
Department of Medicine, Oregon Health & Science University, Portland, OR.
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JS
Obhrai
Schuster Transplant Research Center, Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA. myeung@rics.bwh.harvard.edu.
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Yeung
Schuster Transplant Research Center, Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA. lriella@bwh.harvard.edu.
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Riella
D000818:Animals; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D007155:Immunologic Factors / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000069283:Rituximab / Q000494:pharmacology*
D018951:Antigens, CD20; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D000069283:Rituximab
alloantibody; animal models: murine; basic (laboratory) research/science; fusion proteins and monoclonal antibodies: B cell specific; heart transplantation/cardiology; immunobiology; immunosuppressant; immunosuppression/immune modulation; plasma cells