Induction of antigen-specific Treg cells in treating autoimmune uveitis via bystander suppressive pathways without compromising anti-tumor immunity.
Animals
Autoantigens
/ immunology
Autoimmune Diseases
/ immunology
Bystander Effect
Cell Line, Tumor
Cells, Cultured
Eye Proteins
/ immunology
Immunosuppression Therapy
/ methods
Interleukin-10
/ metabolism
Mice
Mice, Inbred C57BL
Retinol-Binding Proteins
/ immunology
T-Lymphocytes, Regulatory
/ immunology
Transforming Growth Factor beta
/ metabolism
Uveitis
/ immunology
Treg
autoantigen
experimental autoimmune uveitis
immunotherapy
tumor immunity
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
20
11
2020
revised:
03
07
2021
accepted:
06
07
2021
pubmed:
20
7
2021
medline:
13
1
2022
entrez:
19
7
2021
Statut:
ppublish
Résumé
Induction of autoantigen-specific Treg cells that suppress tissue-specific autoimmunity without compromising beneficial immune responses is the holy-grail for immunotherapy to autoimmune diseases. In a model of experimental autoimmune uveitis (EAU) that mimics human uveitis, ocular inflammation was induced by immunization with retinal antigen interphotoreceptor retinoid-binding protein (IRBP). Mice were given intraperitoneal injection of αCD4 antibody (Ab) after the onset of disease, followed by administration of IRBP. EAU was evaluated clinically and functionally. Splenocytes, CD4 The experimental approach resulted in remission of ocular inflammation and rescue of visual function in mice with established EAU. Mechanistically, the therapeutic effect was mediated by induction of antigen-specific Treg cells that inhibited IRBP-driven Th17 response in TGF-β and IL-10 dependent fashion. Importantly, the Ab-mediated immune tolerance could be achieved in EAU mice by administration of retinal autoantigens, arrestin but not limited to IRBP only, in an antigen-nonspecific bystander manner. Further, these EAU-suppressed tolerized mice did not compromise their anti-tumor T immunity in melanoma model. We successfully addressed a specific immunotherapy of EAU by in vivo induction of autoantigen-specific Treg cells without compromising host overall T cell immunity, which should have potential implication for patients with autoimmune uveitis. This study was supported by the Natural Science Foundation of Guangdong Province and the Fundamental Research Fund of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center.
Sections du résumé
BACKGROUND
BACKGROUND
Induction of autoantigen-specific Treg cells that suppress tissue-specific autoimmunity without compromising beneficial immune responses is the holy-grail for immunotherapy to autoimmune diseases.
METHODS
METHODS
In a model of experimental autoimmune uveitis (EAU) that mimics human uveitis, ocular inflammation was induced by immunization with retinal antigen interphotoreceptor retinoid-binding protein (IRBP). Mice were given intraperitoneal injection of αCD4 antibody (Ab) after the onset of disease, followed by administration of IRBP. EAU was evaluated clinically and functionally. Splenocytes, CD4
FINDINGS
RESULTS
The experimental approach resulted in remission of ocular inflammation and rescue of visual function in mice with established EAU. Mechanistically, the therapeutic effect was mediated by induction of antigen-specific Treg cells that inhibited IRBP-driven Th17 response in TGF-β and IL-10 dependent fashion. Importantly, the Ab-mediated immune tolerance could be achieved in EAU mice by administration of retinal autoantigens, arrestin but not limited to IRBP only, in an antigen-nonspecific bystander manner. Further, these EAU-suppressed tolerized mice did not compromise their anti-tumor T immunity in melanoma model.
INTERPRETATION
CONCLUSIONS
We successfully addressed a specific immunotherapy of EAU by in vivo induction of autoantigen-specific Treg cells without compromising host overall T cell immunity, which should have potential implication for patients with autoimmune uveitis.
FUNDING
BACKGROUND
This study was supported by the Natural Science Foundation of Guangdong Province and the Fundamental Research Fund of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center.
Identifiants
pubmed: 34280776
pii: S2352-3964(21)00289-9
doi: 10.1016/j.ebiom.2021.103496
pmc: PMC8318874
pii:
doi:
Substances chimiques
Autoantigens
0
Eye Proteins
0
Retinol-Binding Proteins
0
Transforming Growth Factor beta
0
interstitial retinol-binding protein
0
Interleukin-10
130068-27-8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103496Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Patents (ZL201711202986.0 and ZL201711202988.X) for the reported data are granted in China. The authors have declared that no conflict of interest exists.