Limitations of the pig‐to‐non‐human primate islet transplantation model

In a paper which appears in this issue of Xenotransplantation, Drs Graham and Schuurman discuss potential limitations in the preclinical pig-tonon-human primate (NHP) islet transplantation model [1]. They summarize the results from five different groups, each of which has achieved moderately long-term islet xenograft function using varying approaches, for example, different immunosuppressive regimens, the transplantation of adult or neonatal islets and of islets from wild-type or genetically engineered pig donors, and the transplantation of free or encapsulated islets. In view of their extensive experience with this model, few, if any, investigators are positioned to evaluate the status of the field as well as the authors, who have been in the forefront of developing this model. They and their colleagues in Minneapolis have contributed significantly to such topics as animal enrichment, the use of vascular access ports, and defining safe and effective methods of inducing diabetes in NHPs. Consistent and safe reversal of diabetes in NHPs is currently considered a prerequisite for a clinical trial. The authors make the case that the bar has perhaps been set too high, and we are inclined to agree with them on this point, as we discuss in a forthcoming commentary in this journal [2]. For several reasons, it would be expected that humans receiving pig islets would have superior outcomes to those obtained in NHP models [3,4]. Factors that increase the barriers of the pig-to-NHP model, as compared to pig islet transplantation in humans, include (i) metabolic differences in glucose metabolism (with monkeys maintaining a lower set point for normoglycemia and higher insulin and Cpeptide secretion than in pigs or humans); (ii) body weight loss due to nutritional deficiencies and diarrhea, particularly if a total pancreatectomy has been carried out to induce a state of diabetes; and (iii) a species-specific smaller therapeutic “window” of some of the commonly used immunosuppressive agents (e.g., calcineurin and mTOR inhibitors) possibly resulting in unanticipated side effects. A limitation of the current review is the lack of presentation of recent data from the Minneapolis group. It would have been interesting for the readers to learn whether the authors have modified their protocols since their last report, and, if so, what has been the impact on their results during the past several years. Several groups have achieved long-term (>6 months) pig islet function in NHPs using different induction and maintenance immunosuppressive regimens. We can realistically anticipate that a safe and effective protocol can be developed, especially with experience gained from the clinical testing of novel agents, for example anti-CD40 monoclonal antibodies, thus obviating the need for the administration of anti-CD154 monoclonal antibodies, which, although effective, may prove unacceptable for clinical application. The remaining major issue to be addressed is how to minimize loss (and maximize engraftment) of transplanted pig islets from the instant bloodmediated inflammatory reaction (IBMIR), originally described by Bennet et al. [5]. Our group [6] and others [7] have attempted to elucidate the factors operative in immediate graft destruction (reviewed by van der Windt et al. [8]). In vitro studies have drawn attention to the significant role in the development of IBMIR played by the innate immune response, which may have been underestimated previously [6]. In in vivo studies, the Emory group has investigated the short-term effect of intraportal islet infusion by transplanting islets from different pig sources (e.g., wild type and a1,3galactosyltransferase gene-knockout) concomitantly into different lobes of the liver, thus allowing comparative analysis [7]. Together, these data are enabling conclusions to be made on the effect of genetic engineering of islet-source pigs on the alleviation of IBMIR. In addition, alternative sites for islet xenotransplantation are being explored in NHPs or other experimental animals, some of which may render the islets less susceptible to IBMIR. These sites have included, but have not been limited to, the omental pouch [9], the gastric submucosal space [10], and the subcutaneous tissue [11] sometimes combined with protection by macroalginate encapsulation [12], various scaffolding systems [13], and recently, lymph nodes [14].