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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 为了维持他们的同种异体移植，患者必须严格遵守终身治疗方案，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。在不需要铬免疫抑制的情况下促进同种异体组织接受的策略的发展，不仅可以降低这些威胁生命的并发症的风险，而且可以极大地扩大器官、组织和细胞移植在疾病中的应用，如血红蛋白疾病和遗传免疫缺陷、I型糖尿病，以及可能的其他自身免疫性疾病。 我们继续领导一项工作，以确定猕猴的家庭亲缘程度和MHC匹配程度。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MHC配型增加的情况下，基于共刺激阻断的持久嵌合体的诱导是可以实现的，但即使在MHC完全配型的情况下，排斥反应仍然发生。 我们继续对已知相关程度和MHC匹配程度的恒河猴移植对进行实验。我们的实验表明，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，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。2009年，我们进行了来自骨髓捐献者的同种异体肾移植。到目前为止，考虑到这种方案，我们发现肾移植排斥反应时可以出现持续性的髓系嵌合体。