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 (Vβ6+and Vβ3+) 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-γ (IFN-γ) to host antigens in vitro. These in vitro responses correlated with increased IFN-γ and tumor necrosis factor-α (TNF-α) 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.

An Official American Thoracic Society Research Statement: Noninfectious Lung Injury after Hematopoietic Stem Cell Transplantation: Idiopathic Pneumonia Syndrome

“…The role of alloreactive, donor T cells in the pathogenesis of IPS has been a topic of considerable debate, particularly since the lung has not been considered a classic target organ of acute GVHD. The importance of lymphocytes to lung injury after experimental HSCT has, however, been shown by several groups (5,7,143,144). Donor T cells are critical to the early proinflammatory events associated with lung injury that develops within the first week of HSCT across MHC antigens, whereas in minor H antigen mismatch systems, donor lymphocytes continue to respond to host antigens and contribute to physiologically significant lung injury at later time points (7,144).…”

“…The importance of lymphocytes to lung injury after experimental HSCT has, however, been shown by several groups (5,7,143,144). Donor T cells are critical to the early proinflammatory events associated with lung injury that develops within the first week of HSCT across MHC antigens, whereas in minor H antigen mismatch systems, donor lymphocytes continue to respond to host antigens and contribute to physiologically significant lung injury at later time points (7,144). Furthermore, the infusion of donor T cell clones that recognize allelic differences in cell surface expression of the CD45 molecule into nonirradiated recipients results in a rapidly progressive pulmonary vasculitis within 3 days of their injection (5,145).…”

“…The origin and functional capacity of T cells infiltrating the lung have been examined by using differences in the T cell Vb repertoire between donor and recipient (144). Flow cytometric analysis demonstrated that the TCRab 1 T cells found in the lung 6 weeks after allogeneic HSCT were of donor origin.…”

Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease

“…Epithelial cell apoptosis, the classical GVHD histopathology finding, is not a consistent finding in IPS. 34,35 However, as Cooke et al 36 pointed out, epithelial cell apoptosis is not a requirement of GVHD pathology, and lung biopsies may be difficult to interpret because of nonspecific changes occurring, for example, during mechanical ventilation and suboptimal biopsy specimens owing to the risks associated with the procedure.…”

“…37 Interestingly, it has been observed in a murine model that T-cell depletion of the allograft significantly reduced but did not eliminate pulmonary toxicity. 36 Mature donor T cells were significantly increased in the BAL fluid of mice that received allogeneic T cells as compared to syngeneic controls even in the absence of GVHD, giving weight to the theory that host reactive donor T cells play a central role rather than GVHD per se. In addition, in an allogeneic study using a low T-cell dose (0.2-1.0 Â 10 5 /kg), 6.4% of patients died of IPS, while none of them developed significant GVHD.…”