Efficacy of immunosuppressive drugs in islet xenotransplantation: A study in the pig‐to‐rat model

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Abstract
Several immunosuppressive regime's were used in a pig‐to‐rat islet transplant model, with porcine islet‐like cell clusters placed under the kidney capsule of Lewis rats. The animals were killed 12 days after the implantation. In untreated control rats, a massive infiltration of mononuclear cells occured in the xenograft and no morphologically intact endocrine cells could be seen. Most of the infiltrating cells were large, polygonal, macrophage‐like cells. T‐lymphocytes were found mainly in the peripheral parts of the xenografts. Some NK‐cells were also observed. Treatment with cyclosporin A (CyA, 20 mg/kg BW, p.o.), cyclophosphamide (CYP, 20 mg/kg BW, p.o.), prednisolone (PRED, 20 mg/kg BW, p.o.) and mycophenolate mofetil (MMF, 40 mg/kg BW, p.o.) had little inhibitory effect on the xenograft rejection. In animals given cyclosporin and cyclophosphamide in combination with plasmapheresis there were only occasional infiltrating cells, still only endocrine cells were morphologically intact. Immunosuppression with CyA in combination with rapamycin (RPM, 5 mg/kg BW, i.p.) also had an inhibitory effect on xenograft rejection and there were only a few or a moderate number of cells infiltrating the grafts. However, in this treatment group many morphologically intact endocrine cells were present. The most effective treatment was CyA in combination with 15‐deoxyspergualine (DSG, 10 mg/kg BW, i.m.). The animals so treated had hardly any infiltrating mononuclear cells and the islet xenograft revealed a morphological appearance similar to that observed after transplantation to nude mice‐i.e., intact endocrine tissue, organized in duct‐like structures or cell clusters. All rats had preformed, xenoreactive antibodies in serum directed against membrane antigens on pig ICC. In control animals and animals treated with CyA, a marked rise in antibody levels was found after transplantation. Treatment with CyA and DSG (10 mg/kg BW), CyA and CYP, and protocols including plasmapheresis, resulted in a significant decrease in antibody levels. With the other treatment protocols, the antibody levels remained unchanged.