*Purpose: We have previously shown that interleukin(IL)-17 producing CD4 T cells (Th17 response) dominate in the early anti-donor immune responses of a pig-to-mouse xenogeneic model of islet transplantation. In this study, using a pig-to-humanized mouse islet transplant model, we characterized the early human cellular immune response against porcine islets in untreated transplanted subjects compared to an experimental tolerance therapy cohort.

*Methods: Streptozocin (STZ) induced diabetic, NOD-SCID IL2ry null (NSG) mice with reconstituted human immune systems using human bone marrow-liver-thymus (BLT) tissues were transplanted (day 0) with adult porcine islet cells under the kidney capsule as either untreated or treated with a tolerance therapy (TT) composed of 3 immunosuppressive agents. TT was given peritransplantation as follows: ECDI-fixed donor splenocytes (I.V.) on days -7 and +1; anti-CD20 (I.V.) on days -9 and 0; rapamycin (I.P.) on days -7 to +10. Serum glucose was monitored for graft outcomes. Grafts were harvested upon rejection, defined as sustained hyperglycemia >250 mg/dL, and were analyzed by histology and flow cytometry.

*Results: Using the BLT model, which is known for the most functional, robust human immune system of all humanized mouse models, we first verified adequate reconstitution of human innate and adaptive immune cells (~40% T and ~45% B cells) prior to manipulation. Porcine islets restored normoglycemia in all diabetic subjects within a few days after transplantation. Acute rejection of porcine islets by all untreated humanized mice occurred within 14 to 40 days of transplantation, while >75% of TT treated subjects had not rejected by day 60. Early rejection was characterized by dense graft infiltration of human (h)CD45+ immune cells including hCD19+ B and hCD3+T lymphocytes. Significant numbers of human IL-17A producing hCD44+ CD4 T cells as well as human neutrophils were detected in rejecting islet grafts, but none were seen in treated grafts at day 60. IFN-gamma was not detected in early rejected grafts.

*Conclusions: Acute rejection of porcine islets in this pig-to-humanized mouse model is dominated by the Th17 response. This model provides valuable insight into human immune responses and potential anti-rejection therapeutic strategies against porcine islet xenotransplantation.

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