The lung's friend, the gut's foe

In this issue of Blood, Burman and colleagues provide a detailed experimental study of the ambiguous role of IFNγ in GVHD target-organ pathophysiology.

The development of severe interstitial pneumonitis, characteristic of idiopathic pneumonia syndrome (IPS) as a form of acute graft-versus-host disease (aGVHD) of the lung after allogeneic stem cell transplantation (SCT), is the result of a cascade of events involving conditioning toxicity, chemokine and cytokine production by host and donor cells, the influx of alloreactive donor immune cells, and the damage of host tissue by both major histocompatibility complex (MHC)-dependent and -independent pathways.^1-5  Although similar mechanisms are responsible for the development of aGVHD in other target organs, such as the gastrointestinal (GI) tract, skin, or liver, distribution patterns, kinetics, and severity can vary between lung and other organs both in patients and in experimental studies.

IFNγ, as one of the most prominent Th1 cytokines, has been postulated to be a key player in aGVHD; however, results have been contradictory.^6,7  In this issue of Blood, Burman and colleagues report on a preventive role of IFNγ in the development of IPS in contrast to its detrimental effects on GI-tract GVHD. Using IFNγ-deficient and IFNγ receptor (IFNγR)-deficient animals as donors or recipients in a well-established murine model to induce aGVHD and IPS, they showed that, in the absence of IFNγ production by donor cells, early mortality after allogeneic SCT was increased due to severe interstitial pneumonitis, whereas aGVHD injury to other target organs was unaltered or slightly reduced. The preventive effects of donor-cell-derived IFNγ signaling on IPS development required the expression of IFNγR on lung parenchymal cells, as chimeric mice, in which only the nonhematopoietic-cell compartment expressed this receptor, were protected from IPS; in contrast, only those animals with restricted expression of IFNγR to the hematopoietic-cell compartment developed full disease severity. IFNγ-dependent protection from IPS was not mediated through nitric oxide or indoleamine 2,3 dioxygenase pathways, but rather involved the suppression of adhesion molecules leading to decreased leukocyte adhesion and migration to the lung.

Interestingly, in the same sets of experiments, the authors demonstrated that IFNγ-IFNγR ligand-receptor interactions augmented systemic inflammation and aGVHD of the GI tract. Homing in again on IFNγR being expressed on the parenchymal, but not on the hematopoietic, cell as the critical site of action, these data emphasize the ambiguous role of IFNγ by inducing aGVHD in the gut but preventing it in the lung.

The present study marks a significant advance in understanding the role of IFNγ in SCT immunology, and provides exciting insights into the different regulation of aGVHD pathophysiology of the lung and the GI tract. Using similar models for experimental IPS, previous groups have shown that histopathologic changes of the lung after allogeneic SCT become evident around 2 weeks after transplantation and progressively develop over time.³  The study by Burman and colleagues leads one to speculate that these kinetics may, in part, be due to protective immunodominant effects of elevated IFNγ levels early after transplantation, which then vanish over time, being replaced by other deleterious key players including TNFα. Despite the fact that strain- and model-specific issues cannot be excluded, the data by Burman and colleagues suggest the inhibitory effects of IFNγ signaling pathways as a promising target for preventing and potentially treating IPS.