Inflammation Causes Resistance to Anti-CD20–Mediated B Cell Depletion

L. H. Laws, C. E. Parker, G. Cherala, Y. Koguchi, A. Waisman, M. K. Slifka, M. H. Oberbarnscheidt, J. S. Obhrai, M. Y. Yeung, L. V. Riella

    Research output: Contribution to journalArticlepeer-review

    10 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)3139-3149
    Number of pages11
    JournalAmerican Journal of Transplantation
    Volume16
    Issue number11
    DOIs
    StatePublished - Nov 1 2016

    Keywords

    • alloantibody
    • animal models: murine
    • basic (laboratory) research/science
    • fusion proteins and monoclonal antibodies: B cell specific
    • heart transplantation/cardiology
    • immunobiology
    • immunosuppressant
    • immunosuppressant
    • immunosuppression/immune modulation
    • plasma cells

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Transplantation
    • Pharmacology (medical)

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