1. Blockade of CXCR3 receptor:ligand interactions reduces leukocyte recruitment to the lung and the severity of experimental idiopathic pneumonia syndrome.
- Author
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Hildebrandt GC, Corrion LA, Olkiewicz KM, Lu B, Lowler K, Duffner UA, Moore BB, Kuziel WA, Liu C, and Cooke KR
- Subjects
- Animals, Bone Marrow Cells, Bronchoalveolar Lavage Fluid cytology, Cells, Cultured immunology, Chemokine CXCL10, Chemokine CXCL9, Chemokines, CXC antagonists & inhibitors, Crosses, Genetic, Female, Interferon-gamma biosynthesis, Interferon-gamma blood, Ligands, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Pneumonia etiology, Pneumonia immunology, Pneumonia pathology, Receptors, CCR5 deficiency, Receptors, CCR5 genetics, Receptors, CXCR3, Receptors, Chemokine antagonists & inhibitors, Receptors, Chemokine deficiency, Receptors, Chemokine genetics, Spleen cytology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, Tumor Necrosis Factor-alpha analysis, Chemokines, CXC physiology, Chemotaxis, Leukocyte drug effects, Hematopoietic Stem Cell Transplantation adverse effects, Lung pathology, Pneumonia prevention & control, Receptors, Chemokine physiology, Transplantation, Homologous adverse effects
- Abstract
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-gamma and TNF-alpha 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-gamma (Mig)) and CXCL10 (IFN-gamma-inducible protein 10 (IP-10)) can be induced in a variety of cell types by IFN-gamma alone or in combination with TNF-alpha. 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-gamma-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.
- Published
- 2004
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