TY - JOUR
T1 - A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation
AU - Hildebrandt, Gerhard C.
AU - Duffner, Ulrich A.
AU - Olkiewicz, Krystyna M.
AU - Corrion, Leigh A.
AU - Willmarth, Nicole E.
AU - Williams, Debra L.
AU - Clouthier, Shawn G.
AU - Hogaboam, Cory M.
AU - Reddy, Pavan R.
AU - Moore, Bethany B.
AU - Kuziel, William A.
AU - Liu, Chen
AU - Yanik, Gregory
AU - Cooke, Kenneth R.
PY - 2004/3/15
Y1 - 2004/3/15
N2 - 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-α (TNF-α) 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.
AB - 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-α (TNF-α) 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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U2 - 10.1182/blood-2003-08-2708
DO - 10.1182/blood-2003-08-2708
M3 - Article
C2 - 14615370
AN - SCOPUS:12144286499
SN - 0006-4971
VL - 103
SP - 2417
EP - 2426
JO - Blood
JF - Blood
IS - 6
ER -