Acute lung injury is associated with systemic immune responses involving both cellular and cytokine components. Graft-vs.-host disease is such an immune response generated by donor T cells. In this project, we will use a novel murine model in which a systemic immune reaction initiated by transfer of cloned T lymphocytes of Th1 phenotype culminates in a remarkably selective inflammatory response (including vasculitis, alveolitis, and interstitial inflammation) is comprised of host derived mononuclear cells and activated alveolar macrophages. The central hypothesis that we propose to investigate in this model is hat Th1 cell activation initiates a multi-step sequence of signals that results in selective adherence of activated effector T cells in lung, amplification by selective recruitment of mononuclear cells, and accumulation of activated mononuclear cells and alveolar macrophages. Understanding what controls these events is crucial to defining strategies for modifying these fundamental biologic responses in patients. Our work in progress leads us to postulate that Th1 cell activation results in release of critical pro-inflammatory cytokines and expression of T cell integrins that initiate and direct lung specific inflammation, determined in part by selective up-regulation of vascular adhesion molecules in lung. The mechanisms that confer lung specificity in this model and specify mononuclear cell recruitment to lung are of primary interest to us. We think that the initial Th1 cell derived pro-inflammatory cytokine signals may not only influence vascular adhesion molecules, but also promote a subsequently set of host-derived signals that include chemokines/chemoattractants for mononuclear cells and pro-inflammatory cytokines. The regulation of these """"""""downstream"""""""" events, may have important consequences in terms of a sustained inflammatory responses, and susceptibility to further lung injury.
Our specific aims i n this project are as follows:
Aim 1. To identify mechanisms by which Th1 cells initiate lung inflammation.
Aim 2. To determine mechanisms by which Th1 ell transfer results in selective mononuclear cell (host-derived) recruit to lung.
Aim 3. To examine the effects of T cell transfer on alveolar macrophage function.
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