Allogeneic and xenogeneic islets are rejected by different and specific mechanisms: A study in rodents using a mixed allogeneic‐xenogeneic islet transplantation model

: Indirect evidence suggests that islet alio- and xeno-graft rejections are two qualitatively, and not simply quantitatively, different processes. This, however, has never been clearly shown and a direct in vivo comparison of cell-mediated alio- and xeno-graft rejections has never been made. Therefore, Lewis rats were transplanted with either Wistar-Furth rat islets or fetal porcine islet-like cell clusters (ICC) under the kidney capsule. Other Lewis rats were transplanted with Wistar-Furth rat islets and fetal porcine ICC, which were mixed together into one single graft. Animals were left untreated or were treated with cyclosporin A (CyA, 20 mg/kg b.w., p.o.) daily. Twelve days following transplantation, islet alio- and xeno-graft survival was evaluated morphologically and any cellular infiltration into the grafts was characterized immunohistochemically. In untreated animals, both allogeneic and xenogeneic islets were destroyed by massive cellullar infiltration. The main infiltrating cells in islet allograft rejection were TCR a/(i-positive T-cells. In contrast, the main infiltrating cells in islet xenograft rejection were EDI- and ED2-positive macrophages. In islet xenograft rejection, only a few T-cells were found. In islet allografts removed from rats treated with CyA, many morphologically intact rat islets were found. Only a few infiltrating cells were detected and these were both EDI-positive macrophages and TCR a/p-positive T-cells. In CyA-treated rats transplanted with porcine ICC, we noted a massive infiltration with EDI- and ED2-positive macrophages and TCR a/p-positive T-cells, similar to that observed in untreated animals. No endocrine cells were present. In mixed allogeneic-xenogeneic islet grafts transplanted into CyA-treated rats, many morphologically intact rat islets were found, as evidenced by positive staining for rat MHC class I. However, no porcine ICC remained. The xenogeneic islets in these mixed grafts were destroyed by massive cellular infiltration, similar to that observed after transplantation of xenogeneic islets alone. Obviously, the xenogeneic islets in these mixed grafts were rejected by a cell-mediated process qualitatively different from that of cell-mediated allograft rejection.