Type V Collagen Prevents Lung Allograft Rejection

描述(申请人提供)：肺移植是治疗多种终末期肺部疾病的唯一权威疗法。然而，移植受者的生存受到慢性排斥反应的限制，这种排斥反应称为闭塞性毛细支气管炎(OB)。排斥反应是由受体T细胞识别供体主要组织相容性复合体(MHC)引起的。然而，我们已经报道了排斥反应也涉及对一种天然的V型胶原蛋白的特异性免疫，而对COL(V)的免疫是OB发生的主要危险因素。因此，肺移植排斥反应是一种既有同种异体免疫又有自身免疫的疾病。免疫反应需要淋巴细胞从血流迁移到淋巴结，然后激活的淋巴细胞迁移到炎症/损伤部位。然而，抗COL(V)淋巴细胞迁入和迁出纵隔淋巴结和BALT的机制尚不清楚。此外，最近的研究表明，一组新的T细胞(Th-17)能够在包括肺在内的许多器官中诱导自身免疫性疾病。然而，Th-17细胞在肺移植排斥反应中的自身免疫发病机制中的作用尚未确定。供体同种异体抗原的识别通过直接和间接两种途径进行；急性和慢性两种类型的排斥反应分别归因于每种途径的活性。目前的直接和间接同种异体识别的范例分别基于供体抗原提呈细胞(称为客体白细胞)和受者衍生的抗原提呈细胞(APC)激活受者T细胞的能力。然而，移植肺中的乘客白细胞和体细胞在介导急性排斥反应和OB中的作用尚不清楚。此外，对这些细胞诱导供体抗原和COL(V)特异性Tregs的需求尚未见报道。利用大鼠肺移植模型，本研究通过检测以下特定目的验证了同种免疫诱导的COL(V)自身免疫介导肺移植破坏的假说：目的1.确定COL(V)反应性淋巴细胞用于向纵隔淋巴结和BALT迁移/迁徙的黏附通路是否受到差异调节。目的2.探讨体液免疫和Th-17细胞免疫在抗-ol(V)介导的病理机制中的作用。目的3.探讨同种异体移植排斥反应时，移植肺体细胞和外周血白细胞在Tregs形成过程中的作用及对Col(V)的自身免疫作用。该应用程序将调查肺移植排斥反应的原因，这是导致肺移植受者死亡的主要原因。这项应用还可能确定新的领域，可能允许对这一临床问题进行新的治疗。

DESCRIPTION (provided by applicant): Lung transplantation is the only definitive therapy for many forms of end stage lung disease. However, survival of the transplant recipient is limited by chronic rejection, known as obliterative bronchiolitis (OB). Rejection episodes are initiated by recipient T cells recognizing donor major histocompatibility complexes (MHC). However, we have reported the rejection response also involves specific immunity to a native protein, type V collagen [col(V)], and that immunity to col(V) is a major risk factor for the development of OB. Therefore, lung transplant rejection is a disease if both allo- and autoimmunity. Immune responses require lymphocyte migration from the blood stream to lymph nodes followed by emigration of activated lymphocytes to sites of inflammation/injury. However, the mechanism of anti-col(V) lymphocyte migration and emigration into and from mediastinal lymph nodes and BALT, respectively, are unknown. In addition, recent studies implicate a novel group of T cells (Th-17) able to induce autoimmune disease in many organs, including the lung. However, the role of Th-17 cells in the pathogenesis of autoimmunity that occurs during lung transplant rejection has not been characterized. Recognition of donor alloantigens occurs via two pathways, direct and indirect; and the two types of rejection, acute and chronic, have been attributed to the activity each pathway, respectively. The current paradigm of direct and indirect allorecognition is based on the ability of donor antigen presenting cells (known as passenger leukocytes) and recipient-derived antigen presenting cells (APCs), respectively, to activate recipient T cells. However, the role of passenger leukocytes and somatic cells in lung grafts to mediate acute rejection and OB is unknown. Furthermore, the requirement for these cells to induce Tregs specific for donor antigens and col(V) has not been reported. Utilizing a rat model of lung transplantation, the current proposal tests the hypothesis that alloimmune-induced autoimmunity to col(V) mediates lung transplant destruction by examining the following specific aims: Aim 1. To determine if the adhesion pathways utilized by col(V)-reactive lymphocytes for migration/emigration to mediastinal nodes and BALT are differentially regulated. Aim 2. To determine the contribution of humoral and Th-17 cellular immunity to the pathogenesis of anti-col(V)-mediated pathology. Aim 3. To determine the contribution of somatic cells and passenger leukocytes in the transplanted lung in development of Tregs and autoimmunity to col(V) during allograft rejection. This application will investigate the causes of lung transplant rejection which is the leading cause of death in lung transplant recipients. This application may also identify new areas that may allow for new treatments of this clinical problem.