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Inducible costimulator blockade prolongs airway lumnal patency in a mouse model of obliterative bronchiolitis

Alex KleinJan, Monique Willart UGent, Harmjan Kuipers, Anthony J. Coyle, Henk C. Hoogsteden and Bart Lambrecht UGent (2008) Transplantation. 86(10). p.1436-1444
abstract
Background. In human lung transplantation, chronic rejection is accompanied by obliterative bronchiolitis (013), 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 sonic 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(+)CDI lb(-) and CD103(-)CD11b(+)MHC II+DCs accumulated in the airway epithelium as early as I 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
dendritic cells, Obliterative bronchiolitis, ICOS
journal title
Transplantation
Transplantation
volume
86
issue
10
pages
1436 - 1444
publisher
Lippincott Williams & Wilkins
place of publication
Philadelphia USA
Web of Science type
Article
Web of Science id
000261285600017
JCR category
SURGERY
JCR impact factor
3.816 (2008)
JCR rank
11/148 (2008)
JCR quartile
1 (2008)
ISSN
0041-1337
DOI
10.1097/TP.0b013e3181886baa
language
English
UGent publication?
yes
classification
A1
id
535963
handle
http://hdl.handle.net/1854/LU-535963
date created
2009-04-01 10:23:35
date last changed
2009-04-08 11:38:28
@article{535963,
  abstract     = {Background. In human lung transplantation, chronic rejection is accompanied by obliterative bronchiolitis (013), 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 sonic 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(+)CDI lb(-) and CD103(-)CD11b(+)MHC II+DCs accumulated in the airway epithelium as early as I 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.},
  author       = {KleinJan, Alex and Willart, Monique and Kuipers, Harmjan and Coyle, Anthony J. and Hoogsteden, Henk C. and Lambrecht, Bart},
  issn         = {0041-1337},
  journal      = {Transplantation},
  keyword      = {dendritic cells,Obliterative bronchiolitis,ICOS},
  language     = {eng},
  number       = {10},
  pages        = {1436--1444},
  publisher    = {Lippincott Williams \& Wilkins},
  title        = {Inducible costimulator blockade prolongs airway lumnal patency in a mouse model of obliterative bronchiolitis},
  url          = {http://dx.doi.org/10.1097/TP.0b013e3181886baa},
  volume       = {86},
  year         = {2008},
}

Chicago
KleinJan, Alex, Monique Willart, Harmjan Kuipers, Anthony J. Coyle, Henk C. Hoogsteden, and Bart Lambrecht. 2008. “Inducible Costimulator Blockade Prolongs Airway Lumnal Patency in a Mouse Model of Obliterative Bronchiolitis.” Transplantation 86 (10): 1436–1444.
APA
KleinJan, A., Willart, M., Kuipers, H., Coyle, A. J., Hoogsteden, H. C., & Lambrecht, B. (2008). Inducible costimulator blockade prolongs airway lumnal patency in a mouse model of obliterative bronchiolitis. Transplantation, 86(10), 1436–1444.
Vancouver
1.
KleinJan A, Willart M, Kuipers H, Coyle AJ, Hoogsteden HC, Lambrecht B. Inducible costimulator blockade prolongs airway lumnal patency in a mouse model of obliterative bronchiolitis. Transplantation. Philadelphia USA: Lippincott Williams & Wilkins; 2008;86(10):1436–44.
MLA
KleinJan, Alex, Monique Willart, Harmjan Kuipers, et al. “Inducible Costimulator Blockade Prolongs Airway Lumnal Patency in a Mouse Model of Obliterative Bronchiolitis.” Transplantation 86.10 (2008): 1436–1444. Print.