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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2417-2426.
Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2003-08-2708.
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TRANSPLANTATION
A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation
Gerhard C. Hildebrandt,
Ulrich A. Duffner,
Krystyna M. Olkiewicz,
Leigh A. Corrion,
Nicole E. Willmarth,
Debra L. Williams,
Shawn G. Clouthier,
Cory M. Hogaboam,
Pavan R. Reddy,
Bethany B. Moore,
William A. Kuziel,
Chen Liu,
Gregory Yanik, and
Kenneth R. Cooke
From the Department of Internal Medicine and Pediatrics, Division of Hematology and Oncology, Blood and Marrow Transplantation Program, the Department of Internal Medicine, Division of Pulmonology and Critical Care, and the Department of Pathology, University of Michigan, Ann Arbor, MI; the Department of Pathology, University of Florida School of Medicine, Gainesville, FL; and Section of Molecular Genetics and Microbiology, The University of Texas, Austin.
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– (TNF-) 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.
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