Limitations of the model of porcine islet transplantation in

diabetic nonhuman primates affecting long-term survival

and graft function

Melanie Graham1, Henk-Jan Schuurman1,2

1Schulze Diabetes Institute, Department of Surgery, University of Minnesota,St. Paul, MN, USA, 2Beta-Cell NV, Brussels, Belgium

The model of porcine islet cell transplant to thediabetic macaque is well accepted to study efficacyin and immunological interference. This life-supporting model is therefore considered an inte-gral component in translational research, i.e. inefficacy-toxicity studies before the phase transitionto clinical trials. Diabetes reversal and graftsurvival >180 days has been achieved in incidentalcases, but not in a consistent way. Especially laterafter transplantation complications can becomemanifest that are intrinsic to the model:

• There are metabolic incompatibilities in theinsulin-glucose homeostasis between species.Fasting glucose levels are lower in monkeysthan in pigs or man, and on the other handC-peptide levels are higher. In most studiesefficacy is associated with moderate hypergly-cemia. Insulin secretory capacity in vitro andin vivo is much lower in pigs than in human ormonkeys. Hence, the amount and quality ofporcine islets needed in the pig-to-monkeytransplant setting differ from those in thepig-to-human setting.

• The efficacy-toxicity window of immunosup-pressive drugs is smaller in nonhumanprimates than in humans, in particular forsmall molecular weight xenobiotics. Chronic

immunosuppression can induce gastrointestinaltoxicity and cachexia, as a result of the highexposure to poorly absorbable drugs necessaryto achieve acceptable systemic trough levelscan result ingastrointestinal toxicity, with lipidwasting, malabsorption, and inflammation.This affects the diabetes model, namely areduced challenge of the insulin-producingmachinery thanks to protein and carbohydratemalabsorption, wasting and body weight loss.

• Husbandry and management of nonhumanprimates in chronic survival studies iscomplicated, in particular under conditionsof metabolic perturbations and chronic immu-nosuppression. In our unit an animal refine-ment program has been implemented toachieve optimal well-being. Under such con-ditions long-term survival is facilitated, butalso model limitations become more evident.

We conclude that there are intrinsic aspects in thepig-to-nonhuman primate model of life-supportingislet transplantation that are not apparent in short-term survival studies, but become manifest laterafter transplantation. If long-term survival isachieved, it might not unequivocally reflect goodgraft function, but rather a condition of marginalgraft challenge and insulin secreting activity. Thisphenomenon has consequences for the design andinterpretation of pivotal preclinical studies inpreparation for the phase transition to clinicaltrials.

Berlin Symposium Xenotransplantation 2011 – Abstracts

Xenotransplantation 2012: 19: 2–22Printed in Singapore. All rights reserveddoi: 10.1111/j.1399-3089.2011.00680.x

� 2012 John Wiley & Sons A/S

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