Clinical islet of Langerhans xenotransplantation: How close are we?

The encouraging results recently reported by the Edmonton group in patients receiving allogeneic islet grafts, all of whom achieved at least temporary insulin-independence, has rekindled interest in transplantation of islets of Langerhans as a cure for diabetes [1, 2]. As successful clinical islet transplantation currently requires 2–4 human donors per recipient [1], the shortage of organ donors might prevent most eligible diabetic patients from receiving a graft. Currently, less than 100 cadaveric organ donors become available for clinical transplantation each year in Switzerland. In contrast, the population of type 1 diabetic patients is estimated at approximately 0.2% of the total Swiss population, i.e. around 14,000 persons. Unlimited islet transplants could be performed if a suitable tissue source was identified. Xenotransplantation of porcine islets is a potential solution to this shortage. Although in comparison to pigs, nonhuman primates are genetically closer to humans, but the pig remains the most suitable source of organs for humans due to a number of practical, safety, and ethical reasons [3]. With respect to the treatment of diabetes it is noteworthy that pig islets are known to be metabolically suitable, since pig insulin has for many years been used to treat diabetic patients; its structure differs from human insulin by only one amino acid residue. The implantation of xenogeneic tissue has provoked ethical and epidemiological controversies [4]. Balanced against the benefits of successful xenotransplantation is the possibility of transmission of porcine endogenous retroviruses (PERV) from porcine cells to the xenograft recipient, as infection of human cells has been demonstrated in vitro [5, 6]. However, neither PERV transmission nor clinical infection or disease have been observed in patients who have been exposed to living porcine tissues [7, 8]. The first clinical experience of porcine islet xenotransplantation into human patients was reported by the Swedish group headed by C. Groth in 1992 [9], several years before the identification of PERV. This surgical team transplanted a total of 10 diabetic patients with porcine islets. No reduction in insulin requirement was observed in any of these patients, but porcine C-peptide could be detected [10]. The results of this trial indicated that some xenogeneic islet cells were not acutely rejected in these patients receiving standard pharmacologic immunosuppressive therapy. More recently, a new clinical trial of islet xenotransplantation has been initiated in Mexico by Valdes et al. [11]. Several patients have been transplanted with a combination of porcine islets and Sertoli cells. This trial has provoked skepticism in the scientific community, as it is performed in a country that has no legal regulatory conditions on xenotransplantation and that no pre-clinical animal experiments have been performed [12]. It should therefore be mandatory to perform experiments in relevant pre-clinical models before initiating new clinical trials. As the risk of pig-to-human viral transmission is not yet established or excluded, experiments in large animal models will allow to estimate if this risk is acceptable for the initiation of new clinical trials.