Allogeneic stem cell transplantation (SCT) is the only curative therapy for many patients with malignant and non-malignant diseases. Graft-versus-host disease (GVHD) and acute pulmonary toxicity (idiopathic pneumonia syndrome or IPS) are the two most frequent and life threatening complications of SCT and limit the broader application and efficacy of this powerful treatment strategy.

My scientific interests have been directed toward understanding the immunologic mechanisms that contribute to the development of IPS and acute GVHD following allogeneic SCT. Data generated in my laboratory using mouse models of human disease support the hypothesis that the lung is a target organ of acute GVHD and is susceptible to two distinct, but inter-related pathways of immune-mediated injury. The first is fundamentally dependent upon the interactions of donor T cells and host antigen presenting cells and the generation of allo-antigen specific cellular effectors which home to the lung and cause damage and dysfunction. The second involves aspects of the innate immune response including donor accessory cells (macrophages and neutrophils) and the effects of inflammatory mediators like TNF alpha and endogenous endotoxin as they interact via a “gut-liver-lung” axis of inflammation.  These findings are significant because they support a paradigm shift away from identifying lung injury after SCT solely as an idiopathic clinical syndrome and toward understanding IPS as a process in which the lung is a target of two distinct, but inter-related pathways of immune mediated injury. Although a significant body of data supports a role for both lymphoid and myeloid cellular effectors in the development of IPS, the mechanisms by which donor leukocytes traffic to the lung and other GVHD target organs are still poorly defined. Currently, my laboratory is currently focused on determining the role of chemokines and adhesion molecules in this context.

Importantly, laboratory insights are being actively translated back to the clinical setting in the form clinical protocols wherein agents used initially in mouse models are being used to treat our patients who have developed lung injury after SCT. Promising data from pilot studies have resulted in the development of national multi-center trials that are currently open to accrual. It is anticipated that the development of a clinical-laboratory data base from these trials will result new leads for laboratory investigation and foster the next generation of clinical trials.