LONG-TERM STABLE ISLET FUNCTION IN PRIMATES WITH XENOISLET TRANSPLANT TOLERANCE OFF SUPPRESSION

Abstract

69 Introduction: Pancreatic islet transplantation (PIT) suffers from a high incidence of rejection, early loss of islet mass and detrimental effects of immunosuppressive drugs on islet viability and function. In this study the effects of XIT on serial islet metabolic function were assessed in Primates with IDDM. Methods: Four severely insulinopenic non-human primates (3 Macacca fascicularis and 1 Ceropithecus aethiops) were studied. All required twice daily treatment with 4-10 units of insulin, achieving poor to moderate glucose control (glucose 300-500 mgm%). All were treated with daily insulin at least 6 months before transplant. One animal presented in ketotic coma with severe electrolyte abnormalities and neurologic symptoms. All animals tested had Ketosis and elevated glycosylated hemoglobin with almost undetectable C-peptide levels. Four animals received anti-CD3-immunotoxin infused 2 hr pre-transplant and again on day +1), CsA (20 mg/kg/iv/ 2 hr pretransplant), Neoral, 60 mg/kg/BID and Methylprednisolone 15 mg/kg on day 0 to +3. No immunosuppression of any kind was used beyond day +3 following XIT. One animal served as a control to rule out suppressive effects on autoimmunity. Three recipients were given islets from a single donor (Macaca mulatta). The islets were prepared by the semi-automated technique using Liberase. A mean of 15,000 IE/kg was infused into the portal vein. Several metabolic parameters were evaluated. Results: All transplanted monkeys experienced reversal of IDDM with normalization of all diabetic glycemic parameters 20 days. Current survival after transplantation without evidence of rejection is 120, >320, and >510 days. In the non-transplanted primate given the same immunosuppression but no XIT, diabetic metabolic parameters were unchanged after 6 months follow up. In contrast, all 3 XIT recipients established fasting and non-fasting euglycemia within 1-2 weeks, and none required exogenous insulin after day 10. C-peptide levels increased post-transplant (0.63±0.2 to 3.4±0.45 ng/mL at day 30; 3.95±0.2 at 200 days). Normalization of the intravenous glucose tolerance test was observed at day 15, and no significant differences in the glucose disappearance rate (Km) were observed at day 15, 45, 190 and 365 days post-transplant. No significant reduction of islet mass (evaluated by acute insulin response to glucose) was observed (Pre=2.67±1.1; day 15=38.62±2.8; day 190=34.24±1.1; day 365=38.02). Normal glycosylated hemoglobin levels were observed approx. at day 60 (Pre=9.0±2.4% to 5.0±0.7%). All animals had stable and normal insulin resistance. Conclusions: XIT in severely insulinopenic IDDM primates resulted in restoration of normal glycemic parameters and durable islet mass. All monkeys were free from rejection. Tolerance induction was accomplished with only 3 days of drug administration, resulting in long-term stable islet function. Biopsies showed islet-secreting tissue in the recipient liver and the native pancreas showed destroyed islets. These results show durability of XIT and offer an exciting new potential for IDDM treatment.