1. A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.
- Author
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Hildebrandt GC, Duffner UA, Olkiewicz KM, Corrion LA, Willmarth NE, Williams DL, Clouthier SG, Hogaboam CM, Reddy PR, Moore BB, Kuziel WA, Liu C, Yanik G, and Cooke KR
- Subjects
- Animals, Bronchoalveolar Lavage Fluid cytology, Bronchoalveolar Lavage Fluid immunology, Cytokines metabolism, Female, Lung immunology, Lung pathology, Macrophages immunology, Macrophages pathology, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Monocytes immunology, Monocytes pathology, Pneumonia pathology, RNA, Messenger metabolism, Receptors, CCR2, Receptors, Chemokine genetics, Severity of Illness Index, T-Lymphocytes immunology, T-Lymphocytes pathology, Transplantation, Homologous, Bone Marrow Transplantation adverse effects, Chemokine CCL2 metabolism, Pneumonia immunology, Pneumonia metabolism, Receptors, Chemokine metabolism
- Abstract
Idiopathic pneumonia syndrome (IPS) is a major complication after allogeneic bone marrow transplantation (allo-BMT) and involves the infiltration of donor leukocytes and the secretion of inflammatory cytokines. We hypothesized that leukocyte recruitment during IPS is dependent in part upon interactions between chemokine receptor 2 (CCR2) and its primary ligand monocyte chemoattractant protein-1 (MCP-1). To test this hypothesis, IPS was induced in a lethally irradiated parent --> F1 mouse BMT model. Compared with syngeneic controls, pulmonary expression of MCP-1 and CCR2 mRNA was significantly increased after allo-BMT. Transplantation of CCR2-deficient (CCR2-/-) donor cells resulted in a significant reduction in IPS severity compared with transplantation of wild-type (CCR2+/+) cells and in reduced bronchoalveolar lavage (BAL) fluid cellularity and BAL fluid levels of tumor necrosis factor-alpha (TNF-alpha) and soluble p55 TNF receptor (sTNFRI). In addition, neutralization of MCP-1 resulted in significantly decreased lung injury compared with control-treated allogeneic recipients. Experimental data correlated with preliminary clinical findings; patients with IPS have elevated levels of MCP-1 in the BAL fluid at the time of diagnosis. Collectively, these data demonstrate that CCR2/MCP-1 interactions significantly contribute to the development of experimental IPS and suggest that interventions blocking these receptor-ligand interactions may represent novel strategies to prevent or treat this lethal complication after allo-BMT.
- Published
- 2004
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