MMPs in Alloimmune and Autoimmune Lung Disease

描述(由申请人提供)：这项建议测试了一种假设，即肺间质的基质金属蛋白酶消化会产生COL(V)的抗原片段，从而导致同种异体移植物破坏和/或自身免疫性肺部疾病。肺移植排斥反应和一种称为特发性肺纤维化的自身免疫性肺疾病与T细胞对天然胶原V型胶原的反应非常活跃有关[COL(V)]。在正常情况下，COL(V)被认为是隔离的抗原，即不暴露于肺部局部免疫系统的抗原。然而，包括COL(V)在内的降解间质结缔组织的金属蛋白酶(MMPs)的活性积极参与了包括肺移植在内的各种损伤后的肺重建。在这项建议中，我们假设基质金属蛋白酶的活性负责形成抗原性的COL(V)片段，该片段启动了介导肺破坏的免疫反应。该方案利用了大鼠的同种异体肺移植，这是肺移植排斥反应的主要模型，以及与co！(V)介导的自身免疫性肺部疾病相关的模型。目的：1.为探讨同种异体肺移植排斥反应中基质金属蛋白酶活性与V型胶原免疫识别的关系，对参与肺内胶原(V)片段释放的MMPs和TIMPs的表达进行了研究。目的2.为了确定MMPs在急性排斥反应、闭塞性毛细支气管炎和CoL(V)介导的疾病中的直接作用，将全身和局部抑制MMPs的活性，然后评估排斥反应的病理学和免疫学。目的3.为了确定基质金属蛋白酶活性在COL(V)诱导的自身免疫性肺疾病中的作用，我们将在全身和局部阻断其活性，然后评估COL(V)反应性T细胞在肺内诱导病理的能力。这些研究的最终目标是为患有肺移植排斥反应和自身免疫性肺部疾病的患者确定治疗干预的新靶点。

DESCRIPTION (provided by applicant): This proposal tests the hypothesis that matrix metalloproteinase digestion of the lung interstitium results in antigenic fragments of col(V) that contribute to allograft destruction and/or autoimmune lung disease. Lung allograft rejection and an autoimmune lung disease, known as idiopathic pulmonary fibrosis, are associated with very brisk T cell responses to a native collagen - type V collagen [col(V)]. Under normal conditions, col(V) is considered a sequestered antigen, i.e., one that is not exposed to the local immune system in the lung. However, activity of enzymes known as metalloproteinases (MMPs), which degrade interstitial connective tissues, including col(V), are actively involved in lung re-modeling following a variety of insults including lung transplantation. In this proposal, we postulate that MMP activity is responsible for the formation of antigenic col(V) fragments that prime the immune response that mediates lung destruction. The proposal utilizes transplant of allogeneic lungs in rats, the premier model of lung allograft rejection, and a related model of co!(V)-mediated autoimmune lung disease. There are 3 specific aims: Aim 1. To determine the relationship between MMP activity and immune recognition of type V collagen in lung allografts undergoing rejection, the expression of MMPs and TIMPs involved in release of col(V) fragments in the lung will be characterized. Aim 2. To determine the direct role of MMPs in acute rejection, obliterative bronchiolitis, and col(V)-mediated disease, MMP activity will be inhibited systemically and locally followed by an assessment of pathology and immunology of the rejection response. Aim 3. To determine the role of MMP activity in col(V)- induced autoimmune lung disease, MMP activity will be blocked systemically and locally, followed by an assessment of the ability of col(V)-reactive T cells to induce pathology in the lung. The ultimate goal of these studies is to identify novel targets for therapeutic intervention for patients suffering from lung allograft rejection and autoimmune lung disease.