HOST REACTIVE DONOR T-CELLS ARE ASSOCIATED WITH LUNG INJURY AFTER EXPERIMENTAL ALLOGENEIC BONE-MARROW TRANSPLANTATION

Noninfectious lung injury is common after allogeneic bone marrow trans plantation (BMT), but its association with acute graft-versus-host dis ease (GVHD) is unclear, Using a murine BMT system where donor and host differ by multiple minor histocompatibility (H) antigens, we investig ated the nature of lung injury and its relationship both to systemic G VHD and host-reactive donor T cells. Lethally irradiated CBA hosts rec eived syngeneic BMT or allogeneic (B10.BR) T-cell-depleted (TCD) bone marrow (BM) with and without the addition of T cells. Six weeks after BMT, significant pulmonary histopathology was observed in animals rece iving allogeneic BMT compared with syngeneic controls. Lung damage was greater in mice that received allogeneic T cells and developed GVHD, but it was also detectable after TCD BMT when signs of clinical and hi stologic acute GVHD were absent. In each setting, lung injury was asso ciated with significant alterations in pulmonary function. Mature, don or (V beta 6(+) and V beta 3(+))T cells were significantly increased i n the broncho-alveolar lavage (BAL) fluid of all allogeneic BMT recipi ents compared with syngeneic controls, and these cells proliferated an d produced interferon-gamma (IFN-gamma) to host antigens in vitro. The se in vitro responses correlated with increased IFN-gamma and tumor ne crosis factor-alpha (TNF-alpha) in the BAL fluid. We conclude that all oreactive donor lymphocytes are associated with lung injury in this al logeneic BMT model. The expansion of these cells in the BAL fluid and their ability to respond to host antigens even when systemic tolerance has been established (ie, the absence of clinical GVHD) suggest that the lung may serve as a sanctuary site for these host reactive donor T cells. These findings may have important implications with regard to the evaluation and treatment of pulmonary dysfunction after allogeneic BMT even when clinical GVHD is absent. (C) 1998 by The American Socie ty of Hematology.