Abstract
Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte–associated protein 4–immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4+ and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established.
Original language | English (US) |
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Pages (from-to) | 2312-2323 |
Number of pages | 12 |
Journal | American Journal of Transplantation |
Volume | 16 |
Issue number | 8 |
DOIs | |
State | Published - Aug 1 2016 |
Keywords
- B cell biology
- alloantibody
- animal models: murine
- basic (laboratory) research/science
- fusion proteins and monoclonal antibodies: belatacept
- immunobiology
- immunosuppressant
- immunosuppression/immune modulation
- immunosuppressive regimens
- organ transplantation in general
- rescue
ASJC Scopus subject areas
- Immunology and Allergy
- Transplantation
- Pharmacology (medical)