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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 为了维持同种异体移植，患者必须坚持终身治疗方案，使用昂贵的免疫抑制剂，大大增加心血管疾病、感染和恶性肿瘤的风险。在不需要慢性免疫抑制剂的情况下，开发促进同种异体组织接受的策略可以降低这些并发症的风险，并极大地扩大器官、组织和细胞移植在诸如血红蛋白病和遗传免疫缺陷、1型糖尿病和其他自身免疫性疾病等疾病中的应用。我们继续领导一项工作，以确定猕猴的家庭亲缘关系和MHC匹配的程度。这一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差异的捐赠者和接受者之间进行移植。我们的数据表明，在移植供者和受者之间增加MHC配型，基于共刺激阻断的持久嵌合体诱导是可以实现的。然而，即使MHC完全匹配，仍会发生排斥反应。我们继续进行恒河猴移植配对的实验，已知相关程度和MHV匹配。我们的结果表明，加入CD40或LFA-1定向的共刺激/黏附阻断可以显著增强供体嵌合体的诱导，而且在某些情况下，这种作用是持久的。我们正在继续对这些移植队列中的嵌合体和免疫耐受进行前瞻性监测。