Ex Vivo Induction of Tolerance for Autoimmune Diabetes

描述（由申请人提供）：人体移植已被证明对终末期器官衰竭或关键细胞丧失的患者最有益。例如，人类尸体供体的胰岛移植已经逆转了许多受体的1型糖尿病，使他们不依赖胰岛素。不幸的是，没有足够的人体器官捐献者来满足需求。在150万患有T1D的美国人中，每年只有0.1%的人接受胰岛移植。此外，他们必须无限期地接受慢性免疫抑制。

DESCRIPTION (provided by applicant): Transplantation of human has proved to be most beneficial for patients with end stage organ failure or loss of critical cells. For example, the transplantation of islets from human cadaveric donors has reversed type 1 diabetes for many recipients, making them insulin independent. Unfortunately, there are not nearly enough human organ donors to satisfy the need. Only about 0.1% of the 1.5 million Americans with T1D receive an islet transplant each year. Furthermore, they must receive chronic immune suppression indefinitely. Pig organs could satisfy this immense unmet need. They can be produced under controlled very clean conditions in a cost effective manner. The physiology is very similar to that of humans. The primary obstacle to xenotransplantation, however, is the vigorous rejection of pig tissues. Ximerex has developed a technology for avoiding the need for immune suppression. Recipient cells are grown within the donor pig, during fetal development. Later, the chimeric lymphocytes and tissue graft are transplanted back into the recipient. Observations have shown prolonged function of pig islet tissue in diabetic monkeys without immune suppression. The proposal will transform this promising phenomenon into a xenotransplantation system for application in the clinic. The regulatory cells in the chimeric pig will be identified and quantified. A program for bioproduction and purification of the responsible regulatory cells will be developed. The system will be tested with marrow specimens from human subjects with T1D, where a deficiency of T regulatory cells may contribute to the autoimmune destruction of beta cells. The lessons from the proposed studies would substantially enhance the likelihood that preclinical trials and clinical trials will have successful outcomes. PUBLIC HEALTH RELEVANCE: Type I diabetes (T1D) is due to loss of insulin producing beta cells and effects more than 1.25 million Americans. Ximerex is developing an unlimited source of replacement islets from clean pigs using technology that avoids the need for anti-rejection drugs. This proposal defines the cells that are responsible for long term acceptance, expands and purifies these cells, and determines if such cells are produced from marrow from human subjects with T1D.