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Lung Injury Induced by Alloreactive Th1 Cells Is Characterized by Host-Derived Mononuclear Cell Inflammation and Activation of Alveolar Macrophages¹

Joan G. Clark^2,*,§, David K. Madtes^*,§, Robert C. Hackman^,§, Wei Chen^,§, Martin A. Cheever^,§ and Paul J. Martin^,§

^* Division of Pulmonary and Critical Care Medicine and Division of Oncology, Department of Medicine, and Department of Pathology, University of Washington, Seattle, WA 98195; and ^§ Fred Hutchinson Cancer Research Center, Seattle, WA 98109

We have investigated a murine model of acute lung injury caused by i.v. administration of a T cell clone (CD4⁺, Th1 phenotype) that recognizes Ly5, a polymorphic cell surface glycoprotein expressed on hemopoietic cells. Alloreactive cloned T cells, specific for host Ly5 Ag, cause a mononuclear cell pulmonary vasculitis and interstitial pneumonitis. In further studies of the cellular mechanisms involved in this model, we found that mature host T cells or B cells are not required, since lung injury was comparable in transgenic host mice that lack these cells (RAG-1 knockout). Cloned T cells labeled in vitro with bromodeoxyuridine were localized in inflammation foci in lung, but the majority of cells in the foci were not labeled. Using transgenic mice that constitutively express lacZ, we determined that the mononuclear cell vasculitis is of host cell origin. Alveolar macrophages (AM) from T cell-treated mice spontaneously secreted TNF- in culture, whereas TNF- was not detected in AM cultures from control mice. TNF- production in response to LPS stimulation was significantly higher in AM cultures derived from T cell-treated mice than in those from control mice. Challenge with sublethal doses of LPS resulted in 50% mortality in T cell-treated mice and was associated with augmented AM TNF- production and protein in bronchoalveolar lavage fluid. We conclude that immune activation of T cells of the Th1 phenotype can initiate lung injury characterized by a host-derived mononuclear cell inflammation and activation of AM.

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