The role of the beta chemokines in experimental obliterative bronchiolitis.
Beta chemokines have been implicated in cardiac and renal allograft rejection. This study determined if antibody antagonization of beta chemokines conferred protection against the development of experimental obliterative bronchiolitis (OB) in a heterotopic rat tracheal allograft model. Rat tracheas were transplanted from Brown-Norway or Lewis donors into Lewis recipients. Rats received 200 microg/day of either anti-RANTES or anti-MCP-1 antibody for 14 days. Luminal obstruction and epithelial loss were calculated. Northern blots for MCP-1 and RANTES mRNA expression were performed, and immunohistochemistry for chemokine protein localization. There was a significant increase in airway obstruction in allografts compared to isografts (P < 0.001). Antibody-treated allografts demonstrated an amelioration of airway obstruction from 58% (vehicle allografts) to 26% (anti-RANTES) and 12% (anti-MCP-1), both of which were significant (P < 0.001). Epithelial preservation was increased in both antibody-treated groups (P < 0.001), and increased expression of MCP-1 and RANTES mRNA was present in tracheal allografts by Day 2 and maximal by Day 6. Beta chemokines are expressed during the development of experimental OB, as MCP-1 and RANTES mRNA expression increased with time from transplantation. Both MCP-1 and RANTES are functional in the formation of the fibroproliferative response that characterizes OB in this model, and their antagonization conferred protection against airway obstruction and epithelial loss.
Farivar
Alexander S
AS
Division of Cardiothoracic Surgery, Department of Surgery, University of Washington Medical Center, Seattle, WA 98195, USA.
Krishnadasan
Baiya
B
Naidu
Babu V
BV
Woolley
Steven M
SM
Mulligan
Michael S
MS
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D015152:Blotting, Northern; D001989:Bronchiolitis Obliterans / Q000378:metabolism* / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000276:immunology; D018946:Chemokine CCL5 / Q000276:immunology; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014132:Trachea / Q000473:pathology / Q000637:transplantation; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology
D000906:Antibodies; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019742:Chemokines, CC; D012333:RNA, Messenger