TRANSPLANT TOLERANCE IN NONHUMAN PRIMATES

非人类灵长类动物的移植耐受性

• 批准号: 8357393
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 4.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357393
• 关键词: Adhesions; Allogenic; Allografting; Autoimmune Diseases; Chimerism; Chronic; Data; Development; Disease; Donor person; Family; Funding; Genetic; Grant; Hematopoietic stem cells; Hemoglobinopathies; Immune Tolerance; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infection; Insulin-Dependent Diabetes Mellitus; Lead; Life; Macaca mulatta; Malignant Neoplasms; Modeling; Monitor; National Center for Research Resources; Organ; Patients; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Risk; Source; Stem cell transplant; TNFRSF5 gene; Time; Tissues; Transplant Recipients; Transplantation; Treatment Protocols; United States National Institutes of Health; base; cardiovascular disorder risk; cohort; cost; nonhuman primate; prospective; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. To maintain allografts patients must adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancy. The development of strategies to promote the acceptance of allogenic tissues without the need for chronic immunosuppressant could reduce the risk of these complications and greatly expand the application of organ, tissue, and cellular transplantation for diseases such as the hemoglobinopathies and genetic immunodeficiencies, Type 1 diabetes and other autoimmune diseases. We continue to lead an effort to determine the degree of family relatedness and MHC matching in Rhesus Macaques. This analysis has fundamentally changed the way hematopoietic stem cell transplants are performed and analyzed in the Rhesus model, and have allowed transplants between donors and recipients of know genetic and MHC disparity for the first time. Our data suggest that the setting of increased MHC matching between transplant donors and recipients, Costimulation blockade-based induction of durable Chimerism can be achieved. However, rejection still occurs, even with full MHC matching. We have continued experiments with Rhesus transplant pairs with a known degree of relatedness and MHV matching. Our results indicate that the addition of either CD40-directed or LFA-1 directed Costimulation/adhesion blockade can significantly enhance donor Chimerism induction and that in some cases, it is durable. We are continuing our prospective monitoring of Chimerism and immune tolerance in these transplant cohorts.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 为了维持同种异体移植，患者必须坚持使用昂贵的免疫抑制剂的终生治疗方案，这会大大增加心血管疾病、感染和恶性肿瘤的风险。开发促进接受同种异体组织而不需要长期免疫抑制剂的策略可以降低这些并发症的风险，并大大扩展器官、组织和细胞移植在血红蛋白病、遗传性免疫缺陷、1型糖尿病等疾病中的应用和其他自身免疫性疾病。我们继续致力于确定恒河猴的家族相关性和 MHC 匹配程度。这项分析从根本上改变了在恒河猴模型中进行和分析造血干细胞移植的方式，并首次允许在已知遗传和 MHC 差异的供体和受体之间进行移植。我们的数据表明，通过增加移植供者和受者之间的 MHC 匹配，可以实现基于共刺激阻断的持久嵌合状态的诱导。然而，即使 MHC 完全匹配，排斥反应仍然会发生。我们继续对具有已知相关性和 MHV 匹配程度的恒河猴移植配对进行实验。我们的结果表明，添加 CD40 定向或 LFA-1 定向共刺激/粘附阻断可以显着增强供体嵌合诱导，并且在某些情况下，它是持久的。我们正在继续对这些移植队列中的嵌合现象和免疫耐受进行前瞻性监测。