Vascularized composite islet-kidney transplantation in a miniature swine model

Abstract

Previous work from this laboratory has demonstrated that transplantation of allogeneic thymic tissue as part of a composite vascularized graft is far more successful in terms of both engraftment and long-term survival than transplantation of thymic tissue or cells alone. We have subsequently extended this concept to transplantation of allogeneic islets, comparing survival of islet cell suspensions to that of vascularized composite islet-kidneys (IK), prepared by injection of autologous islets underneath the renal capsule 2-3 months prior to allogeneic transplantation of the composite organ. We have utilized partially inbred miniature swine with defined MHC loci as the experimental large animals for this study, permitting reproducible transplantation across specific MHC barriers. Composite IK have been transplanted successfully across minor and full MHC mismatch barriers, using treatment regimens previously demonstrated to induce long-term tolerance of kidney allografts across these barriers. IK allografts containing > or =5000 islet equivalents (IE)/kg recipient body weight were found capable of reversing surgically induced diabetes, while injection of comparable numbers of purified islets via the portal vein or under the renal capsule did not. Studies are also being directed toward preparation of autologous "thymo-isletkidneys" (TIK), for potential use as xenografts, in which the thymic component is intended to induce tolerance and the islets to reverse diabetic hyperglycemia. The use of both types of composite organ transplants may eventually be applicable to the treatment of type I diabetic patients suffering from end-stage diabetic nephropathy.

Immunosenescence and Immune Response in Organ Transplantation

“…It has been shown that many approaches can enhance thymopoieses including: administration of hormones and cytokines (growth hormone, prolactin, ghrelin, keratinocyte growth factor, vitamin D, and IL-7), androgen ablation, caloric restriction, bone marrow transplantation, and thymic tissue transplantation [131–140]. In the future, gene therapy and stem cell transplants may yield even better results.…”

Subcapsular Fetal Pig Pancreas Fragment Transplantation Provides Normal Blood Glucose Control in a Preclinical Model of Diabetes

“…Kin et al (5) has shown that transplantation of NICC allografts into 15-to 25-kg pigs can achieve normoglycemia, but IVGTT was significantly inferior to nonpancreatectomized animals. In a separate study, syngeneic adult pig islets transplanted under the renal capsule as an islet-kidney composite grafts were capable of reversing diabetes but detailed studies of islet graft function were lacking (16). A more recent study successfully reversed diabetes for over a year after transplantation of intraomental embryonic pig pancreatic tissue in two cynomolgus monkeys.…”

Assessing the Effect of Immunosuppression on Engraftment of Pancreatic Islets

“…To test this idea in an in vivo, preclinical, large animal model, we utilized an established model of vascularized islet transplantation in the miniature swine (23-25). Our previous work in the miniature swine showed that autologous transplantation of islets underneath the renal capsule leads to stable, long-term islet engraftment, and production of a composite organ that we have called an islet-kidney (IK).…”