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The role of B7-H4 in islet transplantation Wang, Xiaojie


Allogeneic pancreatic islet transplantation has the potential to cure type 1 diabetes. One of the barriers to islet transplantation is the alloreactive T-cell response between donors and recipients. Co-stimulatory molecules, which play a major role in regulation of the immune response during graft rejection, may be used to inhibit allograft destruction and generate tolerance. B7-H4 is one such member in the co-stimulatory family to negatively regulate T-cell responses. However, its role in the transplantation field has not been investigated. The aim of this study is to determine the function of B7-H4 in modulating an alloreactive immune response and its signal transduction pathway. The role of B7-H4 in alloimmunity was assessed using a fully major histocompatibility complex mismatched mouse islet transplantation model. Expression of B7-H4 by a recombinant adenovirus in donor allograft islets significantly improved their survival. Moreover, prolonged graft survival was observed in the absence of immunosuppression after secondary transplant, suggesting development of donor specific tolerance. B7-H4 controlled alloreactive immune response by limiting infiltrating cells and increasing Foxp3 expressing cells in the local graft. B7-H4 treatment significantly modulated naturally occurring and inducible regulatory T cells in the periphery and generated hyporesponsiveness to alloantigen. Study of the mechanism by which B7-H4 inhibits T cells revealed interference with activation of ERK, JNK, and AKT, but not through CD3/TCR proximal signal ZAP70 or LCK. This study advances our understanding of the role of the novel co-inhibitory molecule B7-H4 in alloimmune responses. Local expression of B7-H4 prolongs islet allograft survival and generates donor-specific tolerance in vivo, suggesting translational potential for use in reducing immune injury during islet transplantation.

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