TRANSPLANT TOLERANCE IN NONHUMAN PRIMATES

非人类灵长类动物的移植耐受性

• 批准号: 8172322
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172322
• 关键词: Adhesions; Allogenic; Allografting; Autoimmune Diseases; Bone Marrow Transplantation; Chimerism; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Disease; Donor person; Family; Funding; Genetic; Grant; Hematopoietic stem cells; Hemoglobinopathies; Immune Tolerance; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infection; Institution; Insulin-Dependent Diabetes Mellitus; Lead; Life; Macaca mulatta; Malignant Neoplasms; Modeling; Monitor; Myelogenous; Organ; Patients; Regimen; Research; Research Personnel; Resources; Risk; Source; Stem cell transplant; Time; Tissues; Transplantation; Treatment Protocols; United States National Institutes of Health; base; cardiovascular disorder risk; cohort; kidney allograft; 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. 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. 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. We continued to lead an effort to determine the degree of family relatedness and the degree of 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 known genetic and MHC disparity for the first time. Our data suggests that in the setting of increased MHC matching between transplant donors and recipients, costimulation blockade-based induction of durable chimerism can be achievable, but that rejection still occurs, even with full MHC matching. We continued experiments with Rhesus macaque transplant pairs with known degree of relatedness and degree of MHC matching. Our experiments 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. In 2009 we performed renal allograft transplants from the bone marrow donors. To date, given this regimen, we found that we can have persistent myeloid chimerism with rejection of the renal allograft.

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。 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。 我们继续努力确定恒河猴的家族相关程度和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，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是可以实现的，但即使完全MHC匹配，排斥反应仍然会发生。 我们继续用已知相关程度和MHC匹配程度的恒河猴移植对进行实验。 我们的实验表明，添加CD 40定向或LFA-1定向共刺激/粘附阻断剂可以显著增强供体嵌合体诱导，并且在某些情况下，它是持久的。 我们将继续前瞻性监测这些移植队列中的嵌合体和免疫耐受。 在2009年，我们进行了来自骨髓供体的同种异体肾移植。到目前为止，我们发现在这种治疗方案下，移植肾的排斥反应会导致持续的骨髓嵌合体。