Background: Xenogeneic islet transplantation is an emerging therapeutic option for diabetic patients. However, immunological tolerance to xenogeneic islets remains a challenge. Methods: The current study used a pig-to-mouse discordant xenogeneic islet transplant model to examine anti-donor xenogeneic immune responses during early and late rejection, and to determine experimental therapeutic interventions that promote durable pig islet xenograft survival. Results: We found that during early acute rejection of pig islet xenografts, the rejecting hosts exhibited a heavy graft infiltration with B220+ B cells and a robust anti-pig antibody production. In addition, early donor-stimulated IL-17 production, but not IFN-[gamma] production, dominated during early acute rejection. Recipient treatment with donor apoptotic 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide-treated splenocytes (ECDI-SP) significantly inhibited anti-donor IL-17 response, and when combined with B cell depletion and a short course of rapamycin led to survival of pig islet xenografts beyond 100 days in ~65% recipients. Interestingly, treated recipients in this model experienced late rejection between 100 - 200 days posttransplant, which coincided with B cell reconstitution and an ensuing emergence of a robust anti-donor IFN-[gamma], but not IL-17, response. Conclusions: These findings reveal that early and late rejection of pig islet xenografts may be dominated by different immune responses, and that maintenance of long-term xenogeneic tolerance will require strategies that target the temporal sequence of anti-xenogeneic immune responses. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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