COSTIMULATION, CHIMERISM AND TOLERANCE

共刺激、嵌合现象和耐受性

• 批准号: 7349180
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 4.01万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-09 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349180
• 关键词: Primates; family; homologous transplantation; human; immunosuppressive; infection; kidney; success; tissues; transplantation

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 is the preferred treatment for many forms of end-stage organ failure. While short-term results have improved, long-term outcomes remain inadequate. To maintain transplants, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase risks of cardiovascular disease, infections and malignancies. Strategies to promote the acceptance of allogeneic tissues without chronic immunosupression could not only reduce the risk of life-threatening complications, but also greatly expand the application of transplantation. We have developed novel non-myelosuppressive protocols using anti-CD40L and CTLA4-Ig to permit the induction of titratable levels hematopoietic chimerism and robust deletional donor-specific tolerance in rodents. We aim to develop and optimize protocols to induce stable macrochimerism and transplantation tolerance to renal allografts in non-human primates. Even though engraftment of donor cells has been evident at very early time points, donor cells failed to persist beyond 100 days post transplant. We have explored the possibility that failure to develop persistent donor chimerism is due to previous transplant pairs not possessing any degree of family relationship or MHC matching, which are required prior to choosing transplant pairings clinically. A significant barrier existed to adhering to these same selection criteria for non-human primates, in that until recently, the NIH Primate colony at Yemassee, SC, did not collect data on either the degree of relatedness or of MHC disparity between potential transplant donors and recipients. We have undertaken the considerable responsibility of determining both parentage relationships between the animals in the colony and their degree of MHC similarity/disparity. We have thus far typed 142 animals and determined both their familial relationships and degree of MHC disparity. Thus, we can choose our transplant pairs to allow our planned 10 transplants in the coming year to test our costimulation-blockade paradigm for tolerance induction in the setting of known MHC disparity.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。移植是许多终末期器官衰竭的首选治疗方法。虽然短期结果有所改善，但长期结果仍然不够。为了维持移植，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。在无慢性免疫抑制的情况下促进同种异体组织的接受性的策略不仅可以降低危及生命的并发症的风险，而且可以大大扩展移植的应用。 我们已经开发了使用抗CD 40 L和CTLA 4-IG的新型非骨髓抑制方案，以允许在啮齿动物中诱导可滴定水平的造血嵌合体和稳健的缺失供体特异性耐受。我们的目标是开发和优化方案，以诱导稳定的巨嵌合体和移植耐受性的非人灵长类动物的肾同种异体移植。尽管供体细胞的植入在非常早期的时间点已经是明显的，但供体细胞在移植后未能持续超过100天。我们已经探讨了未能形成持续供体嵌合体的可能性，这是由于以前的移植配对不具有任何程度的家庭关系或MHC匹配，这是在临床上选择移植配对之前所必需的。 对于非人灵长类动物，遵守这些相同的选择标准存在一个重大障碍，因为直到最近，位于南卡罗来纳州耶马塞的NIH灵长类动物群落才收集有关潜在移植供体和受体之间的相关程度或MHC差异的数据。我们承担了确定殖民地中动物之间的亲子关系及其MHC相似/差异程度的重大责任。到目前为止，我们已经对142只动物进行了分型，并确定了它们的家族关系和MHC差异程度。因此，我们可以选择我们的移植对，允许我们计划在未来一年进行10次移植，以测试我们的共刺激-阻断范式在已知MHC差异的情况下诱导耐受。