Almost half of the pneumonias after allogeneic BMT are noninfectious in origin and are referred to as IPS. This group has obtained preliminary data in a mouse BMT model that support the hypothesis that IPS after allogeneic BMT is mediated by a cascade of inflammatory cytokines which can be conceptualized as three discrete steps. In step one, both total body irradiation and host alloantigens are factors in activating donor T cells at the time of marrow infusion. In step two, activated donor T cells secrete a number of cytokines, among them interferon-gamma, which is critical for the priming of pulmonary macrophages and monocytes. In step three, primed lung macrophages receive a second signal--either endogenous (gut-derived endotoxin) or exogenous (an inhaled environmental agent)-- and are triggered to secrete large, cytopathic amounts of inflammatory mediators such as TNF, IL-1, and nitric oxide (NO), which injure alveoli and the pulmonary interstitium. Their experimental plan will focus on the developmental pathophysiology of IPS as it relates to each of the three steps of this cytokine cascade.
Their specific aims are to analyze second signals that trigger inflammatory cytokines from pulmonary macrophages after allogeneic BMT and to test specific cytokine inhibitors for the prevention of resultant lung damage, to analyze the role of interferon from donor T cells in priming pulmonary macrophages after allogeneic BMT, and to analyze host TBI and donor/host histoincompatibility as factors in the IPS cytokine cascade following allogeneic BMT.
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