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 language | English (US) |
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Pages (from-to) | 3139-3149 |
Number of pages | 11 |
Journal | American Journal of Transplantation |
Volume | 16 |
Issue number | 11 |
DOIs | |
State | Published - 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)