Lung transplantation has become an increasingly utilized modality for the treatment of endstage lung diseases. However, lung allograft rejection (bronchiolitis obliterans or BO) involves an infiltrate of mononuclear cells, primarily lymphocytes in the perivascular and peribronchiolar connective tissues. It is presumed that persistent injury at these sites, mediated by both cellular and humoral immunity, may lead to long- term irreversible pathologic alterations, including fibrosis and scarring of airways and vascular tissues. Other investigators have demonstrated that collagenous tissues in these same areas undergo extensive remodeling and may contribute to rejection process. Interactions between collagenous tissues and lymphocytes may lead to immune activation. We have reported that lung allograft rejection is associated with the local upregulation of lgG2 antibodies against native and denatured type V collagen. The purpose of the current proposal is to determine the role of type V collagen in the pathogenesis of lung allograft rejection by examining the following specific aims.
Aim 1 is to determine the location of the antigenic regions on the alpha-chains of type collagen.
Aim 2 is to determine if type XI collagen alpha-chains, which are homologous to type V collagen alpha-chains, are also recognized by locally produced IgG2 antibodies. The antigenic regions will be localized to the specific chains of collagens V and XI by Western blotting. The location of the antigenic region within the chain will be determined using peptide mapping with cyanogen bromide and specific proteases.
Aim 3 is to determine if the antigenic peptides isolated from type V collagen and antigenic alpha-chains of type XI collagen induce the lymphocytic bronchitis and vasculitis characteristic of lung allograft rejection. These studies will employ a murine model that we have previously utilized to reproduce the pathology of lung allograft rejection. Mice will receive intratracheal instillations of the antigenic peptides with subsequent histopathological evaluation of the lungs. These studies will provide further insights into the role of connective tissue antigens in the pathogenesis of lung allograft rejection, and could lead to the development of new therapeutic modalities in the treatment of lung allograft recipients.
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