Toxicity in vivo of different immunosuppressive drugs in fetal porcine pancreatic islets.

Abstract

Clinical transplantation of fetal porcine islet-like cell clusters (ICC) to kidney transplanted diabetic patients has shown both morphological and biochemical evidence of prolonged xenograft survival, but no effect 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 differentiation of ICC grafts. In this study, the effects of a number of immunosuppressive drugs on ICC differentiation were investigated. Normoglycemic C57BL/6 nu/nu mice were transplanted with 2x3 microliter ICC under the renal capsule. During a four-week period the animals were treated daily with azathioprine (2.0 mg/kg b.wt.), prednisolone (0.5 mg/kg b.wt.), cyclosporine (5.0 mg/kg b.wt.), cyclophosphamide (5.0 mg/kg b.wt.) 15-deoxyspergualin (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 grafts the mice were injected with 3H-thymidine one hour before killing and slides of the grafts were evaluated with regard to autoradiographical labeling. Other ICC grafts were evaluated by measurement of their insulin and DNA contents. Both the DNA content of ICC grafts and the beta cell labeling index in the cyclosporine animals were significantly decreased. Perfusion experiments with graft-bearing kidneys of cyclosporine-treated animals showed a significantly decreased insulin secretion in response to glucose plus theophylline. None of the other drugs influenced the differentiation of grafted ICC as evaluated in this study. Thus, it is obvious that cyclosporine inhibits both the growth and functional differentiation of transplanted ICC, which might be one reason for the relative lack of success in the clinical transplantation of porcine ICC to diabetic patients.