Assessing the effect of immunosuppression on engraftment of pancreatic islets

In addition to ischemia and immunologic factors, immunosuppressive drugs have been suggested as a possible contributing factor to the loss of functional islets after allogeneic islet cell transplantation. Using our previously described islet-kidney (IK) transplantation model in miniature swine, we studied whether an islet-toxic triple-drug immunosuppressive regimen (cyclosporine+azathioprine+prednisone) affects the islet engraftment process and thus long-term islet function.

Donor animals underwent partial pancreatectomy, autologous islet preparation, and injection of these islets under the autologous kidney capsule to prepare an IK. Experimental animals received daily triple-drug immunosuppression during the islet engraftment period. Control animals did not receive any immunosuppression during this period. Four to 8 weeks later, these engrafted IK were transplanted across a minor histocompatibility mismatched barrier into pancreatectomized, nephrectomized recipient animals at an islet dose of approximately 4500 islet equivalents/kg recipient weight. Cyclosporine was administered for 12 days to the recipients to induce tolerance of the IK grafts and the animals were followed long-term.

Diabetes was corrected by IK transplantation in all pancreatectomized recipients on both the control arm (n=3) and the experimental arm (n=4) of the study and all animals showed normal glucose regulation over the follow-up period. Intravenous glucose tolerance tests performed at 1, 2, and 3 or more months after IK transplantation showed essentially equivalent glycemic control in both control and experimental animals.

In this preclinical in vivo large animal model of islet transplantation, the effect of triple-drug immunosuppression on islet function does not negatively affect islet engraftment as assessed by the long-term function of engrafted islets.