Inducible costimulator blockade prolongs airway luminal patency in a mouse model of obliterative bronchiolitis.
BACKGROUND
In human lung transplantation, chronic rejection is accompanied by obliterative bronchiolitis (OB), a fibrosing inflammatory condition that leads to occlusion of the bronchial lumen and graft failure. The pathogenesis of this disorder is poorly understood, but likely involves antigen presentation by dendritic cells (DC). We studied the presence and activation status of DCs in transplanted tracheas in a mouse model of OB and studied the effect on graft luminal patency of blocking the costimulatory B7RP-1/inducible costimulator (ICOS) pathway.


METHODS
Tracheas from Balb/C or from C57Bl/6 mice were transplanted heterotopically under the dorsal skin of C57Bl/6 mice. Histologic, fluorescence-activated cell sorter, and quantitative-polymerase chain reaction analyses were performed after 1, 2, or 4 weeks. In some groups, treatment with blocking rat anti-mICOS antibodies or irrelevant rat immunoglobulin G was administered during the entire observation period.


RESULTS
After heterotopic transplantation, both CD103+CD11b- and CD103- CD11b+ MHC II+ DCs accumulated in the airway epithelium as early as 1 week after allogeneic (mismatched) but not syngeneic (matched) transplantation. Four weeks after Tx, infiltration with CD11c+ MHCII+ DCs and CD8+ lymphocytes, luminal fibrosis and epithelial damage were more pronounced in the allogeneic than in the syngeneic setting. There was a 10-fold up-regulation of ICOS mRNA and of chemokines involved in T-cell influx in the mismatched setting compared with the matched setting. Strikingly, anti-ICOS treatment without other immunosuppression prevented luminal fibrosis in mismatched transplants.


CONCLUSIONS
Our results suggest that early infiltration by DC occurs in posttransplant OB. Blocking critical costimulatory molecules expressed on DCs, as in the B7RP1-ICOS pathway, prevents epithelial damage and luminal fibrosis.
KleinJan
Alex
A
Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands. a.kleinjan@erasmusmc.nl
Willart
Monique A M
MA
Kuipers
Harmjan
H
Coyle
Anthony J
AJ
Hoogsteden
Henk C
HC
Lambrecht
Bart N
BN
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000503:physiopathology*; D002356:Cartilage / Q000276:immunology / Q000637:transplantation; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D004195:Disease Models, Animal; D000431:Ethanol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000627:therapeutic use; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D014132:Trachea / Q000276:immunology / Q000637:transplantation*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D007074:Immunoglobulin G; C062527:tribromoethanol; D000431:Ethanol