MMPs in Alloimmune and Autoimmune Lung Disease

描述（由申请人提供）：该提案验证了肺间质基质金属蛋白酶消化导致col(V)抗原片段导致同种异体移植物破坏和/或自身免疫性肺病的假设。肺同种异体移植排斥反应和自身免疫性肺部疾病，即特发性肺纤维化，与T细胞对天然胶原- V型胶原的非常活跃的反应有关[col(V)]。在正常情况下，col(V)被认为是一种隔离抗原，即不暴露于肺部局部免疫系统的抗原。然而，降解间质结缔组织（包括col(V)）的金属蛋白酶（MMPs）酶的活性积极参与包括肺移植在内的各种损伤后的肺重建。在这个建议中，我们假设MMP活性负责抗原col(V)片段的形成，抗原col(V)片段启动免疫反应，介导肺破坏。本研究采用同种异体肺大鼠移植，这是同种异体肺移植排斥反应的主要模型，也是一种相关的肺移植模型。（五）介导的自身免疫性肺病。有3个具体目标：为了确定肺同种异体移植排斥反应中MMP活性与V型胶原免疫识别之间的关系，我们将对肺中参与col(V)片段释放的MMPs和TIMPs的表达进行表征。目标2。为了确定MMPs在急性排斥反应、闭塞性细支气管炎和col(V)介导的疾病中的直接作用，MMP活性将被全身和局部抑制，然后对排斥反应进行病理和免疫学评估。目标3。为了确定MMP活性在col(V)诱导的自身免疫性肺部疾病中的作用，将在全身和局部阻断MMP活性，然后评估col(V)反应性T细胞诱导肺部病理的能力。这些研究的最终目的是为患有同种异体肺移植排斥和自身免疫性肺疾病的患者确定新的治疗干预靶点。

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.