LUNG INJURY-INDUCED BY ALLOREACTIVE TH1 CELLS IS CHARACTERIZED BY HOST-DERIVED MONONUCLEAR CELL INFLAMMATION AND ACTIVATION OF ALVEOLAR MACROPHAGES

We have investigated a murine model of acute lung injury caused by i,v , administration of a T cell clone (CD4(+), Th1 phenotype) that recogn izes Ly5, a polymorphic cell surface glycoprotein expressed on hemopoi etic cells. Alloreactive cloned T cells, specific for host Ly5 Ag, cau se a mononuclear cell pulmonary vasculitis and interstitial pneumoniti s. In further studies of the cellular mechanisms involved in this mode l, we found that mature host T cells or B cells are not required, sinc e lung injury was comparable in transgenic host mice that lack these c ells (RAG-1 knockout). Cloned T cells labeled in vitro with bromodeoxy uridine were localized in inflammation foci in lung, but the majority of cells in the foci were not labeled. Using transgenic mice that cons titutively express lacZ, we determined that the mononuclear cell vascu litis is of host cell origin. Alveolar macrophages (AM) from T cell-tr eated mice spontaneously secreted TNF-alpha in culture, whereas TNF-al pha was not detected in AM cultures from control mice. TNF-alpha produ ction in response to LPS stimulation was significantly higher in AM cu ltures derived from T cell-treated mice than in those from control mic e. Challenge with sublethal doses of LPS resulted in 50% mortality in T cell-treated mice and was associated with augmented AM TNF-alpha pro duction and protein in bronchoalveolar lavage fluid. We conclude that immune activation of T cells of the Th1 phenotype can initiate lung in jury characterized by a host-derived mononuclear cell inflammation and activation of AM.