Ex Vivo Induction of Tolerance for Autoimmune Diabetes

描述(申请人提供)：人类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利。例如，来自身体捐赠者的胰岛移植已经逆转了许多受者的1型糖尿病，使他们能够不依赖胰岛素。不幸的是，人类器官捐赠者远远不足以满足这一需求。在150万患有T1D的美国人中，每年只有大约0.1%的人接受胰岛移植。此外，它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得到满足的需求。它们可以在受控的非常清洁的条件下以具有成本效益的方式生产。它的生理结构与人类非常相似。然而，异种移植的主要障碍是猪组织的强烈排斥。 Ximerex已经开发出一种技术，可以避免免疫抑制。受体细胞在胚胎发育期间在供体猪体内生长。随后，嵌合的淋巴细胞和组织移植物被移植回受者体内。观察表明，在没有免疫抑制的情况下，猪胰岛组织在糖尿病猴子体内的作用时间延长。 该方案将把这一有希望的现象转化为可应用于临床的异种移植系统。嵌合猪中的调节细胞将被识别和量化。将制定一项负责调控细胞的生物生产和纯化计划。该系统将用来自患有T1D的人类受试者的骨髓样本进行测试，在T1D患者中，T调节细胞的缺乏可能有助于对β细胞的自身免疫破坏。 拟议研究的经验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细胞丧失所致，影响超过125万美国人。Ximerex正在开发一种来自清洁猪的无限来源的替代胰岛，使用的技术可以避免对抗排斥药物的需要。这项建议定义了负责长期接受的细胞，对这些细胞进行扩增和纯化，并确定这些细胞是否来自患有T1D的人的骨髓。

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.