TOXICITY IN-VIVO OF DIFFERENT IMMUNOSUPPRESSIVE DRUGS IN FETAL PORCINE PANCREATIC-ISLETS

Clinical transplantation of fetal porcine islet-like cell clusters (IC C) to kidney transplanted diabetic patients has shown both morphologic al and biochemical evidence of prolonged xenograft survival, but no ef fect was seen on the insulin requirement of the transplanted patients. One possible explanation for this relative lack of success might have been the influence of the immunosuppressive drugs on the differentiat ion of ICC grafts. In this study, the effects of a number of immunosup pressive drugs on ICC differentiation were investigated. Normoglycemic C57BL/6 nu/nu mice were transplanted with 2x3 mu l ICC under the rena l capsule, During a four-week period the animals were treated daily wi th azathioprine (2.0 mg/kg b.wt.), prednisolone (0.5 mg/kg b.wt.), cyc losporine (5.0 mg/kg b.wt.), cyclophosphamide (5.0 mg/kg b.wt.) 15-deo gyspergualin (5.0 mg/kg b.wt.), leflunomide (30 mg/kg b.wt.) or saline . In order to estimate rates of beta-cell DNA synthesis in the ICC gra fts the mice were injected with H-3-thymidine one hour before killing and slides of the grafts were evaluated with regard to autoradiographi cal labeling; Other ICC grafts were evaluated by measurement of their insulin and DNA contents. Both the DNA content of ICC grafts and the b eta cell labeling index in the cyclosporine animals were significantly decreased, Perfusion experiments with graft-bearing kidneys of cyclos porine-treated animals showed a significantly decreased insulin secret ion in response to glucose plus theophylline, None of the other drugs influenced the differentiation of grafted ICC as evaluated in this stu dy. Thus, it is obvious that cyclosporine inhibits both the growth and functional differentiation of transplanted ICC, which might be one re ason for the relative lack of success in the clinical transplantation of porcine ICC to diabetic patients.