PATHOPHYSIOLOGIC MECHANISMS OF LUNG INJURY AFTER BMT

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DESCRIPTION (Adapted from the applicant's abstract) Almost half of the pneumonias occurring after allogeneic BMT are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). Although a temporal association between IPS and graft versus host disease (GVHD) has been reported, a mechanistic relationship between the two has not been clearly defined. The candidate has obtained preliminary data that supports the hypothesis that this form of lung injury may represent a graft versus host reaction targeting the lung. This reaction is thought to involve a cascade of inflammatory cytokines that can be conceptualized as three distinct steps. In step one, total body irradiation enhances the ability of host alloantigens to stimulate donor T cells at the time of marrow infusion. In step two, activated T cells undergo self stimulation and proliferation while they simultaneously prime pulmonary macrophages by secreting Interferon-gamma (IFNy). During step three, primed lung macrophages receive a second signal - either endogenous (gut derived endotoxin) or exogenous (inhaled/intravenous toxin) - and are triggered to release large amounts of cytotoxic mediators (TNFa, IL-1B, NO) which lead to the destruction of lung tissue. This experimental plan will take a more specific look at lung damage after BMT as it relates to each step of this cytokine cascade. Using a well established murine BMT model, the specific aims are: 1. To evaluate the role of endotoxin as a second signal in the development of IPS and identify the inflammatory mediators responsible for this process by using specific cytokine inhibitors to abrogate lung injury. 2. To analyze the role of IFNy in priming pulmonary macrophages to release proinflammatory cytokines contributing to lung damage. 3. To investigate the role of pre-transplant total body irradiation (TBI) conditioning and degree of donor/host histoincompatibility in the propagation of cytokine dysregulation and eventual pulmonary toxicity. This proposal will combine an intensive laboratory experience with a broad didactic curriculum geared toward acquiring fundamental techniques in cellular and molecular biology and developing a critical approach to transplant immunology. The program will be directly supervised by Dr. Ferrara, whose laboratory is dedicated to understanding the immunopatho-physiologic mechanisms of GVHD. A panel of senior investigators at DFCI will monitor the progress of this project and offer constructive criticism to facilitate preparation for and eventual transition to status of an independent principal investigator.