Transplantation of Purified Islet Cells in Diabetic Rats: III. Immunosuppressive Effect of Cyclosporin

This study examined the effect of cyclosporin on the survival of islet β-cell allografts in streptozocin (STZ)-induced diabetic rats. At a daily oral dose of 5 mg/kg, the agent prevented the rejection of isolated islets, provided they were little contaminated by other pancreatic tissue. The immunosuppressive effect rapidly disappeared after discontinuation of the drug, except when the donor tissue had been pretreated to reduce its nonendocrine content. All recipients of cultured and selected islets maintained a normalized state for >15 wk beyond the 5-wk drug course; this was not the case for shorter periods of treatment. A long-term beneficial effect was also observed in all recipients of purified islet β-cell grafts, which reversed without treatment in half of the cases. Cyclosporin markedly reduced the mononuclear cell infiltration in each type of islet β-cell allograft; aggregates of mixed endocrine islet cells were kept virtually infiltration free. Conditions with minimal initial infiltration were associated with long-term graft survival without the need for continuous pharmacological immunosuppression. We conclude that a short-term cyclosporin treatment can induce long-term survival of allografted islet β-cells, provided the grafts are only slightly contaminated by nonendocrine elements. In rodents, sufficient immunosuppression was achieved by circulating cyclosporin levels of 100–400 ng/ml. Higher concentrations were cytotoxic for cultured islet β-cells and islet non–²-cells. A 5-wk treatment with the immunomodulator ciamexone also resulted in long-term survival of purified β-cell allografts but not of cultured islets. These findings indicate that the success of immunosuppressive treatment in islet cell transplantation can be considerably improved by preparing purified cell grafts of well-defined cellular composition.