TRANSPLANT TOLERANCE IN NON-HUMAN PRIMATES

非人类灵长类动物的移植耐受性

• 批准号: 7562534
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 3.95万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562534
• 关键词: Allogenic; Allografting; Autoimmune Diseases; Biological Preservation; Bone Marrow Transplantation; CD28 gene; Chimerism; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Disease; Donor person; Funding; Genetic; Grant; Hematopoietic; Hemoglobinopathies; Immune Tolerance; Immunity; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infection; Institution; Insulin-Dependent Diabetes Mellitus; Life; Macaca mulatta; Malignant Neoplasms; Methods; Organ; Organ Transplantation; Outcome; Patients; Protocols documentation; Research; Research Personnel; Resources; Risk; Solid; Source; T-Lymphocyte; Therapeutic; Tissues; Transplant Recipients; Transplantation; Treatment Protocols; United States National Institutes of Health; base; cardiovascular disorder risk; end-stage organ failure; genetic pedigree; improved; nonhuman primate; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. While short-term results have improved, long-term outcomes remain inadequate. To maintain their allografts, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancies. The development of strategies to promote the acceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce the risk of these life-threatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies and genetic immunodeficiencies, Type I diabetes, and possibly other autoimmune diseases. In the past year, we have made significant progress towards the development of novel non-myeloablative protocols using CD28 and CD40/CD154 T cell costimulation-blockade-based therapeutics to permit the induction of high levels of hematopoietic chimerism in Rhesus macaques. However, in the setting of full MHC disparity, this chimerism was transient, did not confer immune tolerance to solid organ transplants, and resulted in significant immunodeficiency in transplant recipients. We therefore undertook a pedigree and MHC analysis of the Yerkes colony which has allowed us, in the past year, to perform the first bone marrow transplants between rhesus macaque donors and recipients with known familial relationships and MHC similarity. Our data suggests that in the setting of increased MHC matching between transplant donors and recipients, costimulation blockade-based induction of durable chimerism and resultant tolerance to solid organ transplants is achievable, with preservation of protective immunity.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 移植已成为许多形式的终末期器官衰竭的首选治疗方法。虽然短期成果有所改善，但长期成果仍然不足。 为了维持他们的同种异体移植物，患者必须严格遵守使用昂贵的免疫抑制剂的终身治疗方案，这大大增加了心血管疾病，感染和恶性肿瘤的风险。 发展策略以促进接受同种异体组织而不需要铬免疫抑制，不仅可以降低这些危及生命的并发症的风险，而且还可以大大扩展器官、组织和细胞移植在血红蛋白病和遗传性免疫缺陷、I型糖尿病以及可能的其他自身免疫性疾病等疾病中的应用。 在过去的一年中，我们已经取得了重大进展，对新的非清髓性协议的发展，使用CD 28和CD 40/CD 154 T细胞共刺激阻断为基础的治疗，以允许诱导高水平的造血嵌合体在恒河猴。 然而，在完全MHC不一致的情况下，这种嵌合状态是短暂的，不赋予实体器官移植的免疫耐受性，并导致移植受者的显著免疫缺陷。因此，我们进行了系谱和MHC分析的耶基斯殖民地，使我们能够在过去的一年中，进行第一次骨髓移植恒河猴捐助者和收件人之间的已知的家族关系和MHC相似性。 我们的数据表明，在移植供体和受体之间的MHC匹配增加的情况下，基于共刺激阻断的持久嵌合体诱导和由此产生的对实体器官移植的耐受是可以实现的，同时保留保护性免疫。