Ex Vivo Induction of Tolerance for Autoimmune Diabetes

自身免疫性糖尿病的体外诱导耐受

• 批准号: 7541705
• 负责人: WILLIAM Edward BESCHORNER
• 金额: $ 62.84万
• 依托单位: XIMEREX, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541705
• 关键词: Acute; Address; Allogenic; American; Autoimmune Diabetes; Autoimmune Process; Autoimmunity; Back; Beta Cell; Cells; Chimerism; Chronic; Clinic; Clinical; Clinical Trials; Condition; Disease; ES Cell Line; Environment; Family suidae; Fetal Development; Generations; Goals; Graft Rejection; Heart; Human; Immune; Immune Tolerance; Immune system; In Vitro; Infusion procedures; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Kidney; Liver; Lymphocyte; Marrow; Modeling; Monkeys; Nature; Numbers; Organ; Organ Donor; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiology; Population; Prevention; Production; Public Health; Reaction; Regenerative Medicine; Relative (related person); Small Business Funding Mechanisms; Small Business Innovation Research Grant; Source; Specimen; Stem cells; Sus scrofa; Suspension substance; Suspensions; System; Technology; Testing; Thinking; Tissue Grafts; Tissues; Toxic effect; Transplantation; Xenograft procedure; base; cost effective; design; diabetic; end-stage organ failure; fetal; glucose monitor; human subject; improved; in utero; islet; preclinical study; prevent; programs; success; Acute; Address; Allogenic; American; Autoimmune Diabetes; Autoimmune Process; Autoimmunity; Back; Beta Cell; Cells; Chimerism; Chronic; Clinic; Clinical; Clinical Trials; Condition; Disease; ES Cell Line; Environment; Family suidae; Fetal Development; Generations; Goals; Graft Rejection; Heart; Human; Immune; Immune Tolerance; Immune system; In Vitro; Infusion procedures; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Kidney; Liver; Lymphocyte; Marrow; Modeling; Monkeys; Nature; Numbers; Organ; Organ Donor; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiology; Population; Prevention; Production; Public Health; Reaction; Regenerative Medicine; Relative (related person); Small Business Funding Mechanisms; Small Business Innovation Research Grant; Source; Specimen; Stem cells; Sus scrofa; Suspension substance; Suspensions; System; Technology; Testing; Thinking; Tissue Grafts; Tissues; Toxic effect; Transplantation; Xenograft procedure; base; cost effective; design; diabetic; end-stage organ failure; fetal; glucose monitor; human subject; improved; in utero; islet; preclinical study; prevent; programs; success

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.

描述（由申请人提供）：事实证明，人类的移植对终阶段器官衰竭或关键细胞丧失的患者最有益。例如，从人尸体供体中移植胰岛已为许多接受者逆转了1型糖尿病，使其独立于胰岛素。不幸的是，没有足够的人体器官捐献来满足需求。每年有150万美国人的150万美国人中，只有约0.1％接受胰岛移植。此外，他们必须无限期接受慢性免疫抑制。 猪器官可以满足这种巨大的未满足需求。它们可以以经济有效的方式在受控的非常干净的条件下生产。生理学与人类非常相似。然而，异种移植的主要障碍是对猪组织的剧烈排斥。 Ximerex开发了一项技术，旨在避免进行免疫抑制。在胎儿发育过程中，受体细胞在供体猪内生长。后来，将嵌合淋巴细胞和组织移植物移回接受者。观察结果表明，猪胰岛组织在没有免疫抑制的糖尿病猴中的功能延长。 该提案将把这种有希望的现象转化为用于在诊所应用的异种移植系统。嵌合猪中的调节细胞将被鉴定和定量。将制定一个生物生产和纯化的程序。该系统将通过具有T1D的人类受试者的骨髓标本进行测试，其中T调节细胞的缺乏可能有助于β细胞的自身免疫性破坏。 拟议研究的教训将大大提高临床前试验和临床试验将取得成功的可能性。 公共卫生相关性：I型糖尿病（T1D）是由于胰岛素产生β细胞的损失，并影响超过125万美国人。 Ximerex正在使用避免对抗排斥药的技术开发出一种无限的替代胰岛来源。该建议定义了负责长期接受，扩展和净化这些细胞的细胞，并确定是否是从骨髓中从人类受试者中产生的细胞。