Islet Xenotransplantation and Xeno-antigenicity: studies in a preclinical model

Shortage of human donor organs is the major limiting factor for clinical islet allotransplantation. Xenotransplantation, using the pig as the source of islets is considered a potential solution to this problem. Since the development of pigs homozygous for α1,3-galactosyltransferase gene-knockout (GT-KO), renewed interest exists in the possibility of pig to primate xenotransplantation. This study involved several aspects of islet xenotransplantation in a pig to nonhuman primate model, and xenoantigenicity of donor pig tissue. The first aim was to review the current state of pig to nonhuman primate islet xenotransplantation. The second part focused on the presence of preformed (natural) xeno- antibodies in primate sera against wild-type (WT) pig and GT-KO pig cells. The xeno-antibodies against WT pigs are directed towards both Galα1,3Gal (Gal) and nonGalα1,3Gal (nonGal) epitopes on pig cells. The availability of GT-KO pigs enabled us to study the presence of nonGal antibodies in baboons, cynomolgus monkeys and humans. Different aspects have been studied: The incidence and cytotoxicity of preformed anti-nonGal antibodies have been monitored in these three species. We investigated the development of an elicited nonGal antibody response after GT-KO organ transplantation in baboons. Additionally, the potential difference in anti-nonGal antibody levels in allosensitized compared to nonsensitized humans have been assessed. And we have studied specifically the development of nonGal antibodies in infant humans and infant baboons. The possible implications for clinical xenotransplantation are addressed. The next project was to study porcine islet xenotransplantation in vivo in a nonhuman primate model. The first step was to establish a safe model for induction of diabetes in cynomolgus monkeys. We were then able to study the intraportal transplantation of WT and GT-KO pig islets in diabetic cynomolgus monkeys. An attempt was made to overcome the destruction of a large number of islets shortly after intraportal transplantation (described as Instant Blood-Mediated Inflammatory Reaction [IBMIR] by the Uppsala group), by investigating different ways to reduce this early graft loss. The last aim was to evaluate future perspectives. The current position of clinical islet xenotransplantation is discussed, and a possible alternative to islet xenotransplantation, i.e. islet cell regeneration, is described.

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