Comment on Hildebrandt et al, page 2249
IPS is a frequently fatal noninfectious pulmonary process seen in up to a quarter of the recipients of myeloablative stem cell transplants. Treatment, high-dose steroids, antimicrobials, and supportive care are usually ineffective.
The pathophysiology of lung injury after stem cell transplantation (SCT) is poorly understood. Idiopathic pneumonia syndrome (IPS) has been attributed to many causes, including preparative regimen toxicity, culture-negative infection, immune-mediated injury, and graft-versus-host disease (GVHD). In this issue of Blood, Hildebrandt and colleagues report that donor leukocyte–derived RANTES (a chemokine ligand of the CC chemokine family of proteins that promotes migration of T cells, eosinophils, basophils, and macrophages to sites of inflammation) is significantly elevated in recipients of an allograft after irradiation, compared with syngeneic controls. Elevated mRNA and RANTES protein levels were associated with increased mRNA expression of CCR5 and CCR1 and increased inflammatory cell infiltration into the lung in this mouse model. The importance of donor RANTES was confirmed by the use of RANTES-deficient T cells, where lung injury was significantly reduced but not eliminated.
These data support the idea that IPS is a complex disorder due to a cascade of events. Preparative regimen toxicity (especially from irradiation) generates a proinflammatory environment that damages host tissues, augments the allostimulatory capacity of host dendritic cells, and alters the chemokine environment. Thus, donor T cells may act as effectors and facilitators of lung injury after allogeneic SCT, initiating and/or enabling a cascade, which perpetuates the lung injury. This model suggests that GVHD and IPS share common effector pathways. As importantly, it suggests that targeting T-cell recruitment may be tive in preventing (and to a lesser degree treating) IPS.
Does this mean that IPS is pulmonary GVHD? No. The authors found that GVHD pathology was not significantly altered in the bowel and liver in RANTES-deficient animals when pulmonary damage was significantly decreased. Is IPS an example of a disorder in which an initiating event such as preparative regimen toxicity creates a milieu where bystander allogeneic T cells become activated, further harming damaged tissues and perpetuating the process? What are the relationships among the mechanisms involved in IPS and bronchiolitis obliterans and bronchiolitis obliterans–organizing pneumonia? Further work is clearly needed to better define the pathophysiology and the relationships among these frequently fatal disorders. A better understanding of the mechanisms should lead to effective therapy for these disorders. ▪
