Immunotherapy induced Trm arrest and reverse lung fibrosis

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Immunotherapy induces lung Trm that arrest and reverse lung fibrosis Pulmonary fibrosis is the final common endpoint of a diverse group of diseases such as chronic hypersensitivity pneumonitis, silicosis, radiation injury, asbestosis, rheumatologic diseases, and idiopathic pulmonary fibrosis. To date there are no effective treatments to cure, stop or reverse the unremitting, fatal fibrosis. A critical barrier to treating lung fibrosis is the lack of understanding of the pathways leading to fibrosis as well as those regulating the resolution of fibrosis. One of the first responses to tissue injury is a complex inflammatory response that coordinates tissue repair through the recruitment, proliferation and activation of immune cells, fibroblasts/myofibroblasts and epithelial cells. Wound healing requires the activation of effector cells and myofibroblasts with resultant increased synthesis and deposition of extracellular matrix (ECM). Likewise, effective wound resolution requires the deactivation of these effector cells, the clearance of excess ECM and elimination of the myofibroblasts. Fibrosis results from deviation from one or several of these highly- coordinated pathways and this proposal focuses on the interplay between these overlapping pathways: immune effectors, inflammatory mediators and fibroproliferation in the resolution of fibrosis. The role of the immune system has been repeatedly demonstrated to be intimately and indispensably linked to resolution of fibrosis. Indeed, the Horton lab has robust published and preliminary data demonstrating that vaccination with a vaccinia-based vaccine, after lung fibrosis has already been established, is effective at reversing established pathology as measured by decreased lung collagen deposition, histologic damage and improved lung function. Mechanistically vaccinia vaccination promotes resolution by inducing specific lung tissue resident memory T cells (Trm). Trm play an essential role in mediating protection against tissue specific challenges as well as greatly influence the tissue immune microenvironment. The mechanism by which the Trm regulate tissue specific pathology such as fibrosis is unknown. If lung fibrosis is due to a dysregulated inflammatory response that directs unremitting fibroproliferation, then this pathogenic process can be prevented, arrested and reversed by the establishment of a robust tissue memory T cell response in the lungs. This proposal will employ 3 different models of lung fibrosis to dissect and elucidate not only the mechanisms leading to dysregulated wound repair but also provide mechanistic insight into how Trms reprogram this process to not only arrest disease but promote resolution. Furthermore, we will extend the immunotherapy armamentarium to include the use of additional clinical grade vaccines, listeria and influenza, to provide preclinical data for the use of immunotherapy to prevent, arrest and reverse lung fibrosis. The completion of these studies will provide the insight and preclinical rationale for a novel paradigm shifting approach toward the treatment of lung fibrosis.