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.
