MECHANISMS OF LUNG ALLOGRAFT ACCEPTANCE

描述（由申请人提供）：众所周知，各种器官同种异体移植物的免疫原性和对免疫抑制介导的接受的敏感性不同。肺是免疫原性最强的器官之一，其移植排斥反应率特别高，导致长期结局不佳。肺移植排斥和接受的免疫学要求仍然知之甚少。我们的实验室已经做出了令人惊讶的观察结果，与其他器官形成鲜明对比的是，CD 8+（特别是CD 8 +PD-1+）而不是CD 4 + T细胞的存在对于共刺激阻断介导的肺同种异体移植物的接受至关重要。本申请的总体目标是在小鼠血管化原位肺移植模型中进行机制研究，以研究CD 8 + T细胞在下调对移植物存活有害的同种免疫应答中的作用。在第一个目标中，我们将定义调节性CD 8 + T细胞生成的机制。在第二个目标中，我们将研究抗原呈递细胞在CD 8 + T细胞介导的肺移植物接受中的作用。在第三个目标中，我们将描述通过Toll样受体2（TLR 2）的临床相关先天免疫刺激如何防止CD 8 + T细胞介导的肺同种异体移植物接受。

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.