Joan G. Clark

Mechanisms of Immune Mediated Lung Injury

Lung injury is a significant complication of allogeneic stem cell transplantation. Manifestations of lung injury include non-infectious inflammation of the lung known as idiopathic pneumonia syndrome (IPS). Although the causes are incompletely understood, disordered immune responses similar to those in graft versus host disease (GVHD) may contribute importantly to lung injury. The subset of T helper (Th) cells known as Th1 cells have been implicated in acute GVHD. We have investigated a murine model in which adoptive transfer of cloned alloreactive Th1 cells causes a lung inflammatory response characterized by vasculitis, alveolitis and interstitial inflammation. Our studies have focused on the mechanisms whereby these cells initiate and amplify lung inflammation and injury.

We have shown that Th1 cells selectively adhere to the lung vascular endothelium. This adherence mechanism involves a constitutively expressed receptor on Th1 cells distinct from P-selectin glycoprotein ligand-1 (PSGL-1) that binds to P- and/or E-selectin in lung endothelium. We have also shown that activated Th1 cells which are localized within lung utilize LFA-1 to bind to ICAM-1 in lung. The initial Th1 cell adherence to pulmonary vascular endothelium is a pivotal step in Th1 cell mediated inflammation and lung injury. Thereafter, Th1 cells, activated in vitro or in the lung, release proinflammatory cytokines (including IFN, TNF-; and lymphotoxins) and chemoattractant molecules for mononuclear cells. These mediators may directly promote tissue injury and inflammatory cell recruitment. In addition, Th1 cell derived mediators appear to activate other cells in lung to express adhesion molecules, cytokines and chemokines. We have shown that lung vascular endothelial cells increase expression of the leukocyte adhesion molecules, ICAM-1 and VCAM-1, as well as the IFN- inducible chemokines, IP-10 and MIG. Alveolar macrophages are also activated to produce increased TNF- and mononuclear cell chemoattractants. These responses provide an important means of amplifying the proinflammatory effects of the Th1 cell.

Another manifestation of lung injury after allogeneic transplantation is bronchiolitis obliterans, a condition that leads to airflow obstruction. We have analyzed airflow obstruction occurring in patients who received allogeneic transplants at the Center during the last 10 years. We confirmed that GVHD is a major risk factor, but our studies suggest that there are other unidentified risk factors. We hypothesize that genetic variation in the pathway of the innate immune system may be important in the pathogenesis of bronchiolitis. Our ongoing work is aimed at examining genetic variation among patients and their donors and its relationship to development of bronchiolitis.