The critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients are due to donor T cell infusion and potentiated by cyclophosphamide.

Abstract

We have hypothesized that lung damage occurring in the peri-bone marrow transplant (BMT) period is critical for the subsequent generation of idiopathic pneumonia syndrome (IPS), a major complication following human BMT. The proinflammatory events induced by a common pre-BMT conditioning regimen, cyclophosphamide (Cytoxan ® ) (Cy) and total body irradiation, were analyzed in a murine BMT model. Electron microscopy indicated that Cy exacerbated irradiation-induced epithelial cell injury as early as day 3 after BMT. Allogenicity was an important contributing factor to lung injury as measured by lung wet and dry weights and decreased specific lung compliance. The most significant pulmonary dysfunction was seen in mice receiving both allogeneic T cells and Cy conditioning. IPS was associated with an influx of T cells, macrophages, and neutrophils early post-BMT. Hydroxyproline levels were not increased, indicating that the injury was not fibrotic early post-BMT. As early as 2 h after chemoradiation, host macrophages increased in number in the lung parenchyma.

Acute lung injury after allogeneic stem cell transplantation: is the lung a target of acute graft-versus-host disease?

“…42,49 In one report, mice with IPS showed significant reductions in both dynamic compliance and airway conductance compared with syngeneic controls, consistent with changes expected from both the interstitial and peribronchial infiltrates respectively. 42 Lung injury correlated with the presence but not the severity of GVHD in that study, consistent with clinical reports of IPS in allogeneic SCT recipients whose signs and symptoms of GVHD were mild or absent.…”

“…38,41,48,49 Even under tightly controlled experimental conditions, several patterns of lung injury have emerged, including acute hemorrhagic alveolitis, late onset interstitial pneumonitis and lymphocytic bronchiolitis 38. In several models where the GVH reaction is induced to (1) minor H antigens, (2) class I or class II MHC antigens only or (3) both major and minor H antigens, two major abnormalities are apparent after allogeneic SCT: a dense mononuclear cell infiltrate around both pulmonary vessels ( Figure 1c) and bronchioles ( Figure 1d) and an acute pneumonitis involving the interstitium and alveolar spaces ( Figure 1e).…”

Early onset of acute immune‐mediated lung injury in a child undergoing allogeneic peripheral blood transplantation

“…Interstitial pneumonia was associated with an influx of donor T cells early post bone marrow transplant and related to release of TNF-a, IL1b, and transforming growth factor-b (TGF-b) [7]. Cyclophosphamide and irradiation had a pathogenic role on this damage, but as these authors referred, this was not enough for persistent damage without allogeneic T cells because they found no evidence of significant lung injury in their syngeneic recipients [7].…”

“…The pathogenic role of radiotherapy, chemotherapy, or unknown infectious etiology could not be completely excluded. Being closely related to severe systemic aGVHD, and not isolating any infectious agent, led us to consider, as described in animal models, pulmonary damage by donor T lymphocytes [6,7,8]. This injury should be early and heavily treated like aGVHD, but as the entity has not been clearly recognized yet, this treatment is always delayed for ruling out infectious etiology.…”

“…Subsequent studies failed to show a relationship between these pictures and aGVHD [3,4,5]. However, recent papers have confirmed the role of donor T lymphocytes in immune-mediated inflammatory reactions in the lung [6,7,8]. Whether these reactions should be considered aGVHD or not is often a controversial issue.…”