Fibrosis is the common final pathway for a number of pulmonary disorders such as sarcoidosis, asbestosis, rheumatoid arthritis, scleroderma and idiopathic pulmonary fibrosis. Although pulmonary fibrosis appears to be the end result of chronic unremitting immune activation, often neither the inciting agents of the inflammatory process nor the precise factors driving the fibrotic response are known. In humans, pulmonary fibrosis is associated with lymphocyte infiltration in the parenchyma and alveolar space. However, the precise role of these cells in the disease process has yet to be established. That is, it is unclear if the lymphocytes participate in accelerating fibrosis, are part of an overwhelmed anti-fibrotic negative feed back loop, or both. In this proposal, using a unique mouse model of selective deletion of CD4+ T cell effector subsets, we will test the hypothesis that T helper cells play a critical role in the modulation of pulmonary fibrosis.
In Aim 1 we will determine the role and mechanism by which Thi, Th2, Th17 and regulatory T cells accelerate or prevent the development of fibrosis.
In Aim 2 we will determine the role of alternatively activated macrophages (AAMs). This relatively new subset of macrophages is induced by the Th2 cytokines IL-4/IL-13 and thus we propose that Th2 T cells promote fibrosis in part through the generation of AAM.
In Aim 3 we will employ agents to modulate the T effector response (the TLR agonist LPS and a live viral vaccine) to test the hypothesis that in vivo skewing of T helper responses can be employed as a novel therapeutic strategy to treat or prevent lung fibrosis.
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