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

The model of porcine islet cell transplant to the diabetic macaque is well accepted to study efficacy in and immunological interference. This life-supporting model is therefore considered an integral component in translational research, i.e. in efficacy-toxicity studies before the phase transition to clinical trials. Diabetes reversal and graft survival >180 days has been achieved in incidental cases, but not in a consistent way. Especially later after transplantation complications can become manifest that are intrinsic to the model: • There are metabolic incompatibilities in the insulin-glucose homeostasis between species. Fasting glucose levels are lower in monkeys than in pigs or man, and on the other hand 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 human or monkeys. Hence, the amount and quality of porcine islets needed in the pig-to-monkey transplant setting differ from those in the pig-to-human setting. • The efficacy-toxicity window of immunosuppressive drugs is smaller in nonhuman primates than in humans, in particular for small molecular weight xenobiotics. Chronic immunosuppression can induce gastrointestinal toxicity and cachexia, as a result of the high exposure to poorly absorbable drugs necessary to achieve acceptable systemic trough levels can result ingastrointestinal toxicity, 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. • Husbandry and management of nonhuman primates in chronic survival studies is complicated, in particular under conditions of metabolic perturbations and chronic immunosuppression. In our unit an animal refinement program has been implemented to achieve optimal well-being. Under such conditions long-term survival is facilitated, but also model limitations become more evident. We conclude that there are intrinsic aspects in the pig-to-nonhuman primate model of life-supporting islet transplantation that are not apparent in short-term survival studies, but become manifest later after transplantation. If long-term survival is achieved, it 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.