A novel MyD88 inhibitor attenuates allograft rejection after heterotopic tracheal transplantation in mice.
Animals
Antibodies, Monoclonal
/ therapeutic use
Bronchiolitis Obliterans
CD40 Ligand
/ immunology
Cytokines
/ genetics
Disease Models, Animal
Drug Therapy, Combination
Graft Rejection
/ drug therapy
Humans
Immunologic Factors
/ therapeutic use
Inflammation Mediators
/ metabolism
Lung Transplantation
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Myeloid Differentiation Factor 88
/ antagonists & inhibitors
Piperazines
/ therapeutic use
Thiazoles
/ therapeutic use
Trachea
/ transplantation
Transplantation, Heterotopic
Transplantation, Homologous
Journal
Transplant immunology
ISSN: 1878-5492
Titre abrégé: Transpl Immunol
Pays: Netherlands
ID NLM: 9309923
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
22
04
2018
accepted:
21
11
2018
pubmed:
26
11
2018
medline:
25
6
2019
entrez:
26
11
2018
Statut:
ppublish
Résumé
After lung transplantation, the major complication limiting the long-term survival of allografts is obliterative bronchiolitis (OB), characterized by chronic rejection. Innate immune responses contribute to the development of OB. In this study, we used a murine heterotopic tracheal transplantation mouse model to examine the effects of a newtype of innate immune inhibitor, TJ-M2010-5. Syngeneic tracheal grafts were transplanted heterotopically from C57BL/6 mice to C57BL/6 mice. Allografts from BALB/c mice were transplanted to C57BL/6 mice. The allograft recipients were treated with TJ-M2010-5, and anti-mouse CD154 (MR-1). The grafts were harvested at 7, 14, and 28 days and evaluated by histological and real-time RT-PCR analyses. In untreated allografts, almost all epithelial cells fell off at 7 days and tracheal occlusion reached a peak at 28 days. However, the loss of the epithelium and airway obstruction were significantly improved in mice treated with TJ-M2010-5 combined with MR-1. The relative mRNA expression levels of pro-inflammatory cytokines were upregulated in allogeneic tracheal grafts, and treatment with the two drugs reduced the production of pro-inflammatory cytokines and infiltration of inflammatory cells. In heterotopic tracheal transplantation models, TJ-M2010-5 combined with MR-1 could ameliorate the development of OB.
Sections du résumé
BACKGROUND
After lung transplantation, the major complication limiting the long-term survival of allografts is obliterative bronchiolitis (OB), characterized by chronic rejection. Innate immune responses contribute to the development of OB. In this study, we used a murine heterotopic tracheal transplantation mouse model to examine the effects of a newtype of innate immune inhibitor, TJ-M2010-5.
METHODS
Syngeneic tracheal grafts were transplanted heterotopically from C57BL/6 mice to C57BL/6 mice. Allografts from BALB/c mice were transplanted to C57BL/6 mice. The allograft recipients were treated with TJ-M2010-5, and anti-mouse CD154 (MR-1). The grafts were harvested at 7, 14, and 28 days and evaluated by histological and real-time RT-PCR analyses.
RESULTS
In untreated allografts, almost all epithelial cells fell off at 7 days and tracheal occlusion reached a peak at 28 days. However, the loss of the epithelium and airway obstruction were significantly improved in mice treated with TJ-M2010-5 combined with MR-1. The relative mRNA expression levels of pro-inflammatory cytokines were upregulated in allogeneic tracheal grafts, and treatment with the two drugs reduced the production of pro-inflammatory cytokines and infiltration of inflammatory cells.
CONCLUSIONS
In heterotopic tracheal transplantation models, TJ-M2010-5 combined with MR-1 could ameliorate the development of OB.
Identifiants
pubmed: 30472390
pii: S0966-3274(18)30049-2
doi: 10.1016/j.trim.2018.11.006
pii:
doi:
Substances chimiques
5-(3-(4-(4-benzylpiperazin-1-yl)-N-(4-phenylthiazol-2-yl))propanamide
0
Antibodies, Monoclonal
0
Cytokines
0
Immunologic Factors
0
Inflammation Mediators
0
Myeloid Differentiation Factor 88
0
Piperazines
0
Thiazoles
0
CD40 Ligand
147205-72-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-6Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.