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* Department of Pediatrics, Blood and Marrow Transplantation Program, and
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109;
Perlmutter Laboratory, Children’s Hospital, and Harvard Medical School, Boston, MA 02115;
Klinik IV Paediatrische Haematologie und Onkologie, Medizinische Universitaetsklinik Freiburg, Freiburg, Germany;
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Section of Molecular Genetics and Microbiology, University of Texas, Austin, TX 78712; and
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Department of Pathology, University of Florida School of Medicine, Gainesville, FL 32610
Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication after allogeneic stem cell transplantation (allo-SCT) that responds poorly to standard immunosuppressive therapy. The pathophysiology of IPS involves the secretion of inflammatory cytokines including IFN-
and TNF-
along with the recruitment of donor T cells to the lung. CXCR3 is a chemokine receptor that is expressed on activated Th1/Tc1 T cell subsets and the expression of its ligands CXCL9 (monokine induced by IFN- (Mig)) and CXCL10 (IFN--inducible protein 10 (IP-10)) can be induced in a variety of cell types by IFN- alone or in combination with TNF-. We used a lethally irradiated murine SCT model (B6 
bm1) to evaluate the role of CXCR3 receptor:ligand interactions in the development of IPS. We found that Mig and IP-10 protein levels were significantly elevated in the bronchoalveolar lavage fluid of allo-SCT recipients compared with syngeneic controls and correlated with the infiltration of IFN--secreting CXCR3+ donor T cells into the lung. The in vivo neutralization of either Mig or IP-10 significantly reduced the severity of IPS compared with control-treated animals, and an additive effect was observed when both ligands were blocked simultaneously. Complementary experiments using CXCR3–/– mice as SCT donors also resulted in a significant decrease in IPS. These data demonstrate that interactions involving CXCR3 and its primary ligands Mig and IP-10 significantly contribute to donor T cell recruitment to the lung after allo-SCT. Therefore, approaches focusing on the abrogation of these interactions may prove successful in preventing or treating lung injury that occurs in this setting.
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