Interferon-gamma in Experimental Pulmonary Fibrosis

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DESCRIPTION (provided by applicant): Chronic fibrotic lung disease occurs in a variety of clinical settings, including the idiopathic interstitial pneumonias, as well as in many of the rheumatic diseases. We previously developed a model of acute T cell-mediated pulmonary injury, which results in severe alveolar injury, leading to significant respiratory impairment and death within a few days. This model involves the adoptive transfer of activated CD8+ T cells into recipient animals expressing the specific antigen on alveolar epithelial cells. In contrast with the acute lung injury occurring after transfer of wild-type CD8+ T cells, we have recently found that chronic inflammation and fibrosis may result from the CD8+ T cell recognition of alveolar antigen in the absence of IFN-gamma exclusively in the antigen-specific cell population, and have found that these T cells induce a totally different pattern of lung injury, including a more chronic pattern of inflammation and, importantly, interstitial and intraluminal fibrosis. This was accomplished by using IFN-gamma-deficient CD8+ T cell clones for adoptive transfer, which results in inflammation and fibrosis that evolves over a period of 2-4 weeks after administration. This very exciting result represents the first animal model of pulmonary fibrosis that does not involve an exogenous toxin, and which evolves entirely from a single, well-defined molecular interaction, the T cell receptor recognition of antigen on alveolar epithelial cells. In order to understand the mechanisms which underly the resolution of acute pulmonary inflammation which results directly from expression of IFN-gamma by the antigen-specific CD8+ T cell, and the factors which may lead to chronic inflammation and fibrosis in its absence, we propose the following Specific Aims:1. To characterize the impact of IFN-gamma expressed by CD8+ T cells on input and host T lymphocyte activities in vivo.2. To characterize the specific effects of IFN-gamma expressed by CD8+ T cells on host macrophages and the impact on progression to chronic pulmonary inflammation.3. To characterize the specific effects of CD8+ T cell recognition in the absence of IFN-gamma on antigen-presenting epithelial cells and the impact on progression to chronic pulmonary inflammation.