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丢失的患者最有益。例如，从人类尸体供体移植胰岛已经逆转了许多接受者的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赠者来满足需求。在150万患有T1D的美国人中，每年只有约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。 猪的器官可以满足这一巨大的未满足的需求。它们可以在受控的非常清洁的条件下以成本有效的方式生产。生理学与人类非常相似。然而，异种移植的主要障碍是猪组织的强烈排斥。 Ximerex开发了一种技术，可以避免免疫抑制的需要。胚胎干细胞在供体猪体内生长，在胎儿发育期间。随后，嵌合淋巴细胞和组织移植物被移植回受体。观察结果表明，在没有免疫抑制的情况下，糖尿病猴的猪胰岛组织功能延长。 该提案将把这一有希望的现象转化为异种移植系统，以应用于临床。将鉴定和定量嵌合猪中的调节细胞。将开发负责调节细胞的生物生产和纯化程序。该系统将使用T1 D受试者的骨髓样本进行测试，其中调节性T细胞的缺乏可能导致β细胞的自身免疫破坏。 从拟议的研究中吸取的教训将大大提高临床前试验和临床试验取得成功结果的可能性。 公共卫生相关性：I型糖尿病（T1D）是由于产生胰岛素的β细胞的损失，影响超过125万美国人。Ximerex正在开发一种无限量的替代胰岛来源，来自清洁猪，使用的技术避免了抗排斥药物的需要。该提案定义了负责长期接受的细胞，扩增和纯化这些细胞，并确定这些细胞是否来自T1D人类受试者的骨髓。

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.