MECHANISMS OF LUNG ALLOGRAFT ACCEPTANCE

描述(由申请人提供)：众所周知，不同的器官移植在免疫原性和对免疫抑制介导的接受的敏感性上存在差异。肺是免疫原性最强的器官之一，移植物排斥率特别高，导致长期效果不佳。对同种异体肺移植排斥和接受的免疫学要求仍然知之甚少。我们的实验室做出了令人惊讶的观察，与其他器官形成鲜明对比的是，CD8+(特别是CD8+PD-1+)的存在而不是CD4+T细胞的存在，对于共刺激阻断介导的同种异体肺移植的接受至关重要。这项应用的总体目标是在小鼠带血管的原位肺移植模型中进行机制研究，以探讨CD8+T细胞在下调有害于移植物存活的同种异体免疫反应中的作用。在第一个目标中，我们将定义CD8+T细胞生成的调节机制。在第二个目标中，我们将研究抗原提呈细胞在CD8+T细胞介导的同种异体肺移植接受中的作用。在第三个目标中，我们将描述临床相关的通过Toll样受体2(TLR2)的先天免疫刺激如何阻止CD8+T细胞介导的同种异体肺移植的接受。 公共卫生相关性：接受肺移植的患者比其他器官接受者的长期存活率更差。这项赠款申请探索了接受肺移植的免疫学基础。这一应用的结果可以提高肺移植受者的长期存活率。

DESCRIPTION (provided by applicant): It is well established that various organ allografts differ in their immunogenicity and susceptibility to immunosuppression-mediated acceptance. Lungs are among the most immunogenic organs with particularly high rates of graft rejection leading to poor long-term outcomes. Immunologic requirements for lung allograft rejection and acceptance remain poorly understood. Our laboratory has made the surprising observation that, in stark contrast to other organs, the presence of CD8+ (specifically CD8+PD-1+) rather than CD4+ T cells, is critical for co-stimulatory blockade-mediated acceptance of lung allografts. The overall goal of this application is to perform mechanistic studies in the mouse vascularized orthotopic lung transplantation model to investigate the role of CD8+ T cells in down-regulating alloimmune responses deleterious to graft survival. In the first aim we will define mechanisms of regulatory CD8+ T cell generation. In the second aim we will investigate the role of antigen presenting cells in CD8+ T cell-mediated lung allograft acceptance. In the third aim we will characterize how clinically relevant innate immune stimulation through Toll-like receptor 2 (TLR2) prevents CD8+ T cell-mediated lung allograft acceptance. PUBLIC HEALTH RELEVANCE: Patients that receive a lung transplant have worse long-term survival than other organ recipients. This grant application explores the immunologic basis for lung transplant acceptance. Results from this application could improve the long-term survival of lung transplant recipients.