A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.
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.
Hildebrandt
Gerhard C
GC
Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA.
Duffner
Ulrich A
UA
Olkiewicz
Krystyna M
KM
Corrion
Leigh A
LA
Willmarth
Nicole E
NE
Williams
Debra L
DL
Clouthier
Shawn G
SG
Hogaboam
Cory M
CM
Reddy
Pavan R
PR
Moore
Bethany B
BB
Kuziel
William A
WA
Liu
Chen
C
Yanik
Gregory
G
Cooke
Kenneth R
KR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine