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

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

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    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)
    JournalAmerican Journal of Transplantation
    DOIs
    StateAccepted/In press - 2016

    Fingerprint

    B-Lymphocytes
    Inflammation
    Intravenous Immunoglobulins
    Allografts
    Half-Life
    Antibodies
    Pharmacokinetics
    B-Lymphoid Precursor Cells
    Toll-Like Receptors
    Cell- and Tissue-Based Therapy
    Autoimmune Diseases
    Transplantation
    Bone Marrow
    Monoclonal Antibodies
    Antigens
    Drug Therapy

    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
    • Medicine(all)
    • Pharmacology (medical)
    • Transplantation

    Cite this

    Laws, L. H., Parker, C. E., Cherala, G., Koguchi, Y., Waisman, A., Slifka, M., ... Riella, L. V. (Accepted/In press). Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion. American Journal of Transplantation. https://doi.org/10.1111/ajt.13902

    Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion. / Laws, L. H.; Parker, C. E.; Cherala, G.; Koguchi, Y.; Waisman, A.; Slifka, Mark; Oberbarnscheidt, M. H.; Obhrai, J. S.; Yeung, M. Y.; Riella, L. V.

    In: American Journal of Transplantation, 2016.

    Research output: Contribution to journalArticle

    Laws, LH, Parker, CE, Cherala, G, Koguchi, Y, Waisman, A, Slifka, M, Oberbarnscheidt, MH, Obhrai, JS, Yeung, MY & Riella, LV 2016, 'Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion', American Journal of Transplantation. https://doi.org/10.1111/ajt.13902
    Laws, L. H. ; Parker, C. E. ; Cherala, G. ; Koguchi, Y. ; Waisman, A. ; Slifka, Mark ; Oberbarnscheidt, M. H. ; Obhrai, J. S. ; Yeung, M. Y. ; Riella, L. V. / Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion. In: American Journal of Transplantation. 2016.
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    AU - Cherala, G.

    AU - Koguchi, Y.

    AU - Waisman, A.

    AU - Slifka, Mark

    AU - Oberbarnscheidt, M. H.

    AU - Obhrai, J. S.

    AU - Yeung, M. Y.

    AU - Riella, L. V.

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