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

T细胞免疫球蛋白和粘蛋白结构域3在肺移植中的作用

• 批准号: 7806144
• 负责人: Josalyn L Cho
• 金额: $ 5.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806144
• 关键词: Acute; Address; Allografting; Antigen-Presenting Cells; Binding; Bronchiolitis Obliterans; Bronchoalveolar Lavage; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell-Mediated Cytolysis; Cells; Chronic; Cicatrix; Complex; Data; Dendritic Cells; Development; Equilibrium; Galactose Binding Lectin; Generations; HLA Antigens; Human; Immune; Immune system; Immunoglobulins; Immunologics; Immunosuppression; In Vitro; Injury; Investigation; Laboratories; Ligands; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Lymphocyte antigen; Mediating; Modeling; Molecular Profiling; Mucins; Mus; Operative Surgical Procedures; Organ Transplantation; Outcome; Pathway interactions; Patients; Pattern; Play; Protein Family; Proteins; Recruitment Activity; Regulation; Role; Solid; Staging; Surface; T-Cell Proliferation; T-Lymphocyte; Techniques; Th1 Cells; Therapeutic; Trachea; Transplantation; Transplantation Tolerance; Transplanted tissue; allograft rejection; animal data; cell type; cytokine; cytotoxicity; effective therapy; genetic regulatory protein; granzyme B; human disease; improved; in vivo; insight; lung allograft; lung injury; mortality; mouse model; novel; novel diagnostics; perforin; peripheral blood; research study; response; therapeutic target

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.

描述（由申请人提供）：肺移植是目前唯一可用于各种终末期肺部疾病的治疗选择。移植后患者生存的主要限制是肺的慢性排斥反应，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）是在分化的Th1细胞的表面上优先表达的蛋白。动物数据表明，Tim3可能在移植耐受中起关键作用，但从未在肺移植中进行过研究。我们的实验室有几个小鼠模型，这将使我们能够专门解决Tim3在肺移植中的作用。初步数据表明，在没有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，有助于介导肺移植耐受，并且Tim3活性的操纵可以增强移植功能和存活。我们进一步假设Tim3的作用是上调和下调的，以控制Th1应答的产生和终止，并且这种作用可能部分是由于CD8+淋巴细胞和抗原呈递细胞之间的相互作用。具体而言，我们寻求确定以下内容：1）使用BO的鼠模型，Tim3在体内肺同种异体移植物排斥中的作用，2）Tim3在体外和体内调节CD8+效应T淋巴细胞中的作用，以及（3）肺移植后人肺中白细胞和抗原呈递细胞上Tim3的表达谱以及这些发现与BO存在的相关性。这些实验将全面描述Tim3在BO发展和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发现新的BO诊断标志物，并提供有关Tim3作为潜在治疗靶点的见解，以改善肺移植的结果。肺移植是目前治疗各种终末期肺部疾病的唯一治疗选择。尽管在外科技术和免疫抑制方面取得了进展，但与其他实体器官移植相比，肺移植患者的结局更差。对调节免疫系统的途径（如Tim3）的研究可能有助于发现新的治疗方法，从而改善肺移植患者的预后。