Immune Profiling

虽然移植对许多终末期器官衰竭患者来说是挽救生命的疗法，但从长远来看 移植的结果仍然不充分，慢性器官排斥反应的发生率很高， 需要使用昂贵的免疫抑制剂进行终身治疗，这些药物会显著增加风险 心血管疾病、感染和恶性肿瘤的风险。制定战略以促进 接受不需要铬免疫抑制的同种异体组织不仅可以减少 这些危及生命的并发症，也大大扩展了器官、组织和组织的应用 细胞移植。在啮齿动物模型中，使用CD28和CD40/154T细胞共刺激的策略 在混合嵌合体诱导环境中的阻断导致了对骨髓和 同种异体器官移植。在这项提案中，我们将测试这种联合的共刺激阻断/嵌合体诱导 策略，以便严格确定翻译的要求 结果在啮齿动物模型中给予临床护理。我们建议的统一目的是在临床上发展 在保持免疫的同时诱导同种异体实体器官移植耐受的适用方案 移植受者的能力。为了实现这一目标，详细了解 移植供者和受者之间MHC差异的程度，移植的免疫后果， 允许有效扩展和分析过继免疫疗法的方案是 必填项。这一核心将侧重于提供这些关键的跨项目评价，这些评价将对 本提案中描述的两个项目的成功。

While transplantation represents life-saving therapy for many patients with end-stage organ failure, longterm outcomes of transplant remain inadequate, with high rates of chronic organ rejection and the equirement for life-long therapy with 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. In rodent models, strategies using CD28 and CD40/154 T cell costimulation blockade in the setting of mixed-chimerism induction have led to robust tolerance to both bone marrow and solid organ allografts. In this proposal, we will test this combined costimulation blockade/chimerisminduction strategy in Rhesus macaques in order to rigorously determine the requirements to translate the results in rodent models to clinical care. The unifying purpose of our proposal is to develop clinically applicable protocols for the induction of tolerance to solid organ allografts while preserving immune competence in the transplant recipient. In order to accomplish this goal, a detailed understanding of the degree of MHC disparity between transplant donors and recipients, the immune consequences of transplant, and the protocols that allow the efficient expansion and analysis of adoptive immunotherapeutics are required. This core will be focused on providing these key cross-project evaluations that will be crucial to the success of both of the projects described in this proposal.