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Am J Transplant ; 16(11): 3139-3149, 2016 11.
Article in English | MEDLINE | ID: mdl-27265023

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.


Subject(s)
Antigens, CD20/immunology , B-Lymphocytes/immunology , Graft Rejection/prevention & control , Graft Survival/immunology , Inflammation/immunology , Lymphocyte Depletion , Rituximab/pharmacology , Animals , Female , Graft Rejection/etiology , Heart Transplantation/adverse effects , Immunoglobulins, Intravenous/administration & dosage , Immunologic Factors/pharmacology , Inflammation/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
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