We propose an extensive study on the role of the immune system in the pathogenesis of lung fibrosis. We will focus mainly on chronic pulmonary T cell responses, since various lymphokines produced by activated T cells are known to play key roles in regulating the state of activation of macrophages, and in directly or indirectly controlling fibroblast / epithelial cell growth. .gammadelta (Vgamma/Vdelta1) resident pulmonary T cells will be addressed in detail. These gammadelta T cells are strong producers of KGF and INF- gamma; they constitute a homogenous population and have a human equivalent population. We will take full advantage of the gammadelta transgenic mice which express these KGF producer T cells, and investigate the role of gammadelta T pulmonary lymphocytes in regulating the fibrotic process. The activation of Vgamma6/Vdelta1 T cells will be achieved using various antigens, including synthetic pyrophosphate compounds which activate gammadelta T cells in both mice and humans. .alphabeta resident pulmonary T cells will be approached under the assumption that different subsets of T cells are not functionally equivalent in enhancing or down-modulating the fibrotic process: . CD4 + Th1 cells which produce INF-gamma might have the opposite effect of CD8+ cytotoxic T cells. . CD4 + Th2 cells which produce large amounts of IL-4, could favor the recruitment of other activated T cells which require this lymphokine for local proliferation but are unable to secrete it (e.g. gammadelta T cells). . CD8+ T cells specific for peptide or happen + Class I MHC complexes presented by epithelial cells can provoke a massive epithelial tissue destruction. In this proposal, the effects of these subpopulations of T cells, either alone, or in putatively synergistic or antagonistic combinations, will be thoroughly investigated by: 1). the use of transgenic+ and knock-out mice (in which various populations of T cells are missing); 2). the genetic control of T cell reactivity by MHC presentation (which will shift the immune responsiveness toward a specific T cell subset). Experiments will be accomplished by using a wide range of molecular biology, cellular immunology, and histochemistry techniques. Based on the information obtained in the experiments described above, this project also proposes to develop at least one experimental disease system, in which the interaction between the immune system and the fibrotic process can be modulated only with the help of T cell specific ligands. As an expansion of these studies, we will focus on developing a scientifically sound position in the immune therapy of lung fibrosis.
Showing the most recent 10 out of 38 publications
