The role of T cell immunoglobulin and mucin domain 3 in lung transplantation

描述(由申请人提供)：肺移植是目前可用于各种终末期肺部疾病的唯一治疗选择。移植后患者生存的主要限制是慢性肺排斥，称为闭塞性细支气管炎(BO)。T细胞免疫球蛋白和粘蛋白结构域3(TIM3)是一种在分化的Th1细胞表面优先表达的蛋白。动物实验表明，TIM3可能在移植耐受中起关键作用，但在肺移植中从未被研究过。我们的实验室有几个小鼠模型，可以让我们专门研究TIM3在肺移植中的作用。初步数据表明，在缺乏TIM3的情况下，免疫平衡倾向于耐受而不是排斥。我们的假设是，TIM3是一种重要的调节蛋白，有助于介导肺移植的耐受，并且控制TIM3的活性可以提高移植功能和存活率。我们进一步假设，TIM3的作用是上调和下调的，以控制Th1反应的产生和终止，这种作用可能部分是由于CD8+淋巴细胞和抗原提呈细胞之间的相互作用。1)TIM3在BO小鼠体内肺移植排斥反应中的作用；2)TIM3在体外和体内调节CD8+效应T淋巴细胞的作用；(3)TIM3在肺移植后人肺内白细胞和抗原提呈细胞上的表达及其与BO存在的相关性。这些实验将全面描述TIM3在BO的发生和CD8+T细胞介导的排斥反应中的作用。我们的研究结果与人类疾病的相关性可能会确定BO的新诊断标记物，并为TIM3作为改善肺移植结果的潜在治疗靶点提供见解。肺移植是目前治疗各种终末期肺部疾病的唯一选择。尽管外科技术和免疫抑制技术取得了进步，但与其他实体器官移植相比，肺移植患者的预后更差。研究调节免疫系统的途径，如TIM3，可能有助于发现新的治疗方法，从而改善肺移植后患者的预后。

DESCRIPTION (provided by applicant): Lung transplantation is currently the only therapeutic option available for a variety of end-stage pulmonary disorders. The major limitation to patient survival following transplantation is chronic rejection of the lung, called bronchiolitis obliterans (BO). T cell immunoglobulin and mucin domain 3 (Tim3) is a protein preferentially expressed on the surface of differentiated Th1 cells. Animal data suggests that Tim3 may play a critical role in transplantation tolerance, but it has never been studied in lung transplantation. Our laboratory has several mouse models that will allow us to specifically address the role of Tim3 in lung transplantation. Preliminary data suggests that in the absence of Tim3, immunologic balance leans toward tolerance rather than rejection. Our hypothesis is that Tim3 is an important regulatory protein that helps mediate tolerance in lung transplantation and that manipulation of Tim3 activity could enhance transplant function and survival. We further hypothesize that the effects of Tim3 are up- and down-regulated in order to control the generation and termination of a Th1 response, and that this effect may in part be due to interactions between CD8+ lymphocytes and antigen presenting cells. Specifically, we seek to determine the following: 1) the role of Tim3 in lung allograft rejection in vivo using a murine model of BO, 2) the role of Tim3 in regulating CD8+ effector T lymphocytes both in vitro and in vivo, and (3) the expression profile of Tim3 on leukocytes and antigen presenting cells in human lungs following lung transplantation and the correlation of these findings with the presence of BO. These experiments will comprehensively delineate the role of Tim3 in the development of BO and in CD8+ T cell-mediated rejection. Correlation of our findings with human disease may identify new diagnostic markers for BO and offer insights about Tim3 as a potential therapeutic target to improve outcomes in lung transplantation. Lung transplantation is currently the only therapeutic option available for a variety of end-stage pulmonary disorders. Despite advances in surgical techniques and immunosuppression, patients with lung transplantation suffer from worse outcomes compared with other solid organ transplants. Investigation of pathways that regulate the immune system, such as Tim3, may help to discover novel therapies that could improve outcomes for patients following lung transplantation.