335

Limitations of the model of porcine islet transplantation in diabetic nonhuman primates affecting long-term survival and graft function

Melanie L. Graham, Henk-Jan Schuurman

Schulze Diabetes Institute, Surgery, University of Minnesota, Minneapolis, MN, United States

The model of porcine islet cell transplant to the diabetic macaque is well accepted to study efficacy of islet cell preparations and immune intervention. Diabetes reversal and graft survival >180d has been achieved in incidental cases, but not in a consistent way. Especially later after transplantation complications can become manifest:

• Metabolic incompatibilities in the insulin-glucose homeostasis between species. Fasting glucose levels are lower in monkeys than in pigs or man, while C-peptide levels are higher. In most studies efficacy is associated with moderate hyperglycemia. Insulin secretory capacity in vitro and in vivo is much lower in pigs than in man or monkeys. Hence, the amount and quality of porcine islets needed in pig-to-monkey transplantation differ from those in the pig-to-human setting.

• The efficacy-toxicity window of (low-MW xenobiotic) immunosuppressants is smaller in nonhuman primates than in humans. Chronic immunosuppression can induce gastrointestinal toxicity as a result of high exposure to poorly absorbable drugs necessary to achieve acceptable systemic exposure, with lipid wasting, malabsorption, and inflammation. This affects the diabetes model, namely a reduced challenge of the insulin-producing machinery thanks to protein and carbohydrate malabsorption, wasting and body weight loss.

• Management of nonhuman primates in chronic survival studies is complicated, in particular under conditions of metabolic perturbations and chronic immunosuppression. We implemented an animal refinement program to achieve optimal well-being, which facilitates both long-term survival and the emergence of model-specific limitations.

In conclusion, the pig-to-nonhuman primate model of life-supporting islet transplantation shows limitations that are not apparent in short-term survival studies, but become manifest later after transplantation. Long-term survival might not unequivocally reflect good graft function, but rather a condition of marginal graft challenge and insulin secreting activity. This phenomenon has consequences for the design and interpretation of pivotal preclinical studies in preparation for the phase transition to clinical trials.