title: Host reactive donor T cells are associated with lung injury after experimental allogeneic bone marrow transplantation.
abstract: Noninfectious lung injury is common after allogeneic bone marrow transplantation (BMT), but its association with acute graft-versus-host disease (GVHD) is unclear. Using a murine BMT system where donor and host differ by multiple minor histocompatibility (H) antigens, we investigated the nature of lung injury and its relationship both to systemic GVHD and host-reactive donor T cells. Lethally irradiated CBA hosts received 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 receiving 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 histologic acute GVHD were absent. In each setting, lung injury was associated with significant alterations in pulmonary function. Mature, donor (Vbeta6(+) and Vbeta3(+)) T cells were significantly increased in the broncho-alveolar lavage (BAL) fluid of all allogeneic BMT recipients compared with syngeneic controls, and these cells proliferated and produced interferon-gamma (IFN-gamma) to host antigens in vitro. These in vitro responses correlated with increased IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) in the BAL fluid. We conclude that alloreactive donor lymphocytes are associated with lung injury in this allogeneic 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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute; the Department of Pathology, Brigham and Women's Hospital; the Division of Pediatric Pulmonology, Children's Hospital, Boston, MA, 20115, USA. kenneth_cooke@dfc.harvard.edu
authors.forename: K R
authors.initials: KR
authors.lastname: Cooke
authors.forename: W
authors.initials: W
authors.lastname: Krenger
authors.forename: G
authors.initials: G
authors.lastname: Hill
authors.forename: T R
authors.initials: TR
authors.lastname: Martin
authors.forename: L
authors.initials: L
authors.lastname: Kobzik
authors.forename: J
authors.initials: J
authors.lastname: Brewer
authors.forename: R
authors.initials: R
authors.lastname: Simmons
authors.forename: J M
authors.initials: JM
authors.lastname: Crawford
authors.forename: M R
authors.initials: MR
authors.lastname: van den Brink
authors.forename: J L
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D006648:Histocompatibility; D007371:Interferon-gamma / Q000032:analysis; D008168:Lung / Q000276:immunology / Q000473:pathology; D008170:Lung Compliance; D008171:Lung Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008808:Mice, Inbred CBA; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D011828:Radiation Chimera; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D015778:Minor Histocompatibility Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma