Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 7, Issue 12, Pages 2663-2674Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1600-6143.2007.01996.x
Keywords
coinhibition; costimulatory blockade; islet transplantation; rejection; tolerance
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Complex interactions between positive and negative cosignaling receptors ultimately determine the fate of the immune response. The recently identified coinhibitory receptor, B and T lymphocyte attenuator (BTLA), contributes to regulation of autoimmune and potentially alloimmune responses. We investigated the role of BTLA in a fully major histocompatibility complex-mismatched mouse islet transplant model. We report that anti-BTLA mAb (6F7) alone does not accelerate graft rejection. Rather, while CTLA4lg alone improved allograft survival, the addition of anti-BTLA mAb to CTLA4lg led to indefinite (> 100 days) allograft survival. Immediately after treatment with anti-BTLA mAb and CTLA4lg, islet allografts showed intact islets and insulin production despite a host cellular response, with local accumulation of Foxp3+ cells. We clearly demonstrate that combined therapy with anti-BTLA mAb and CTLA4lg mice induced donor-specific tolerance, since mice accepted a second donor-specific islet graft without further treatment and rejected third party grafts. CTLA4lg and anti-BTLA mAb limited the initial in vivo proliferation of CFSE-labeled allogeneic lymphocytes, and anti-BTLA mAb enhanced the proportion of PD-1 expressing T cells while depleting pathogenic BTLA+ lymphocytes. We conclude that targeting the BTLA pathway in conjunction with CTLA4lg costimulatory blockade may be a useful strategy for promoting immunological tolerance in murine islet allografts.
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