Role of T Cells in Lung Disease in Systemic Sclerosis

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DESCRIPTION (provided by applicant): Pulmonary fibrosis is a major cause of death in scleroderma. Progressive pulmonary fibrosis in scleroderma is part of a mature, stable pathologic network that is ongoing in the lungs of certain patients, rather than the end of a unidirectional cascade. This pathology includes multiple components, linked in multiple ways. Preliminary work suggests that CD8+ T cells may be an essential component in this pathologic network. The hypothesis of this work is that T cells are essential to progressive pulmonary fibrosis in scleroderma, causing lung fibrosis through production of pro-fibrotic cytokines and growth factors as well as stimulation of TGF-betaa production and activation, alternative activation of macrophages and lung inflammation. The strategy is to delete T cells and monitor changes in profibrotic pathways in vivo, as well as clinical benefit on lung function. These experiments will include in-depth analyses of the effects of T cells on profibrotic pathways, assessed at the level of gene expression, protein expression and signal transduction. The expected outcome is that depletion of T cells will reduce T cell production of IL-4 and other profibrotic growth factors and reduce production and activation of TGF-beta. It will reduce alternative activation of alveolar macrophages and lung inflammation. These changes will be accompanied by arrest of pulmonary fibrosis. In this application, patients will receive alefacept therapy for 12 months, with bronchoalveolar lavage done at time 0, 6, and 12 months. Alefacept is a humanized LFA-3/IgG1 fusion protein that depletes CD2+ cells, which are largely T cells, through apoptosis, without T cell activation. The specific aims are given: 1) Show that alefacept therapy depletes T cells in the lungs of scleroderma patients and that T cell depletion stabilizes lung fibrosis; 2) Show that two major profibrotic pathways - IL-4 production and signaling and TGF-beta production, activation and signaling - are T cell-dependent processes in scleroderma lung disease; and 3) Show that alternative activation of macrophages and lung inflammation are T cell-dependent processes in scleroderma lung disease. The new information that is gained will advance knowledge of T-cell dependent mechanisms of pulmonary fibrosis in scleroderma.