Reversal of naturally occurring diabetes in primates by unmodified islet xenografts without chronic immunosuppression

Background. Isolated pancreatic islet transplantation (IPITx) is an attract ive alternative for treatment of insulin-dependent diabetes mellitus (IDDM) . How-ever, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are s usceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successfu l in promoting stable primate kidney transplant tolerance in our experience , we considered that tolerance induction with IT might be duplicated in IPI Tx. Materials and Methods. Three monkeys with spontaneous IDDM (two Macaca fasc icularis and one Ceropithecus aethiops) were treated with xenogeneic pancre atic islets (Macaca mulatta). Intrahepatic islet transplantation was perfor med at a mean of 13136+/-3860 islet equivalents/kg. Islet xenograft accepta nce was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT tr eatment was supplemented with cyclosporine and steroids administered on day s 0 through 4. No additional immunosuppression was given thereafter. Two ad ditional control macaques with spontaneous IDDM received the immunosuppress ive protocol without islet infusion. Results, All recipients were restored to stable euglycemia, off exogenous i nsulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptid e, and glycosylated hemoglobin tests confirmed the restoration of normal gl ucose homeostasis after islet transplantation. All three islet recipients h ave remained euglycemic at 410, 255, and 100 days of follow-up despite reco very of peripheral T cells to normal levels. In contrast, none of the contr ols presented changes in the diabetic status 4 and 8 months after treatment . Conclusions. These results represent the first demonstration in nonhuman pr imates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved a nd more cost-effective therapy for IDDM.