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Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection
Author(s) -
Young J. S.,
Chen J.,
Miller M. L.,
Vu V.,
Tian C.,
Moon J. J.,
Alegre M.L.,
Sciammas R.,
Chong A. S.
Publication year - 2016
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13761
Subject(s) - cytotoxic t cell , immunology , medicine , antibody , germinal center , t cell , immune system , b cell , transplantation , biology , biochemistry , in vitro
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 ( CTLA 4‐Ig) blocks T cell activation and consequently inhibits T‐dependent B cell antibody production, and the current paradigm is that CTLA 4‐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 CTLA 4‐Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA 4‐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 CTLA 4‐Ig minimally inhibited graft‐specific CD 4 + and T follicular helper responses. Remarkably, delaying CTLA 4‐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 CTLA 4‐Ig. Collectively, our studies revealed the unexpected efficacy of CTLA 4‐Ig for inhibiting ongoing B cell responses even when the graft‐specific T cell response was robustly established.