Correction of Defective T-Regulatory Cells From Patients With Crohn's Disease by Ex Vivo Ligation of Retinoic Acid Receptor-α.
Adult
Animals
Antineoplastic Agents
/ pharmacology
Case-Control Studies
Cell Culture Techniques
Cell Movement
/ drug effects
Cells, Cultured
Crohn Disease
/ immunology
Female
Forkhead Transcription Factors
/ metabolism
Gene Expression
/ drug effects
Heterografts
Humans
Immunosuppressive Agents
/ pharmacology
Integrins
/ genetics
Intestinal Mucosa
/ immunology
L-Selectin
/ metabolism
Lymphocyte Activation
Male
Mice
Mice, SCID
Middle Aged
Organic Chemicals
/ pharmacology
Retinoic Acid Receptor alpha
/ agonists
Sirolimus
/ pharmacology
T-Lymphocytes, Regulatory
/ drug effects
Transcriptome
/ drug effects
Tretinoin
/ pharmacology
Cell Therapy
IBD
Immune Regulation
Tissue Engineering
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
30
07
2018
revised:
07
01
2019
accepted:
11
01
2019
pubmed:
3
2
2019
medline:
14
5
2019
entrez:
3
2
2019
Statut:
ppublish
Résumé
Crohn's disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities. We measured levels of the integrin α4β7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor-α (RARA), and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts. We found that Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. The pathway that regulates the expression of integrin subunit α is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4β7, as well as CD62L and FOXP3, compared with cells incubated with rapamycin or rapamycin and all-trans retinoic acid. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines, and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labeled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium. Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. Incubation of patients' ex vivo expanded Treg cells with rapamycin and an RARA agonist induced expression of α4β7 and had suppressive and migratory activities in culture and in intestinal xenografts in mice. These cells might be developed for treatment of CD. ClinicalTrials.gov, Number: NCT03185000.
Sections du résumé
BACKGROUND & AIMS
Crohn's disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities.
METHODS
We measured levels of the integrin α4β7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor-α (RARA), and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts.
RESULTS
We found that Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. The pathway that regulates the expression of integrin subunit α is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4β7, as well as CD62L and FOXP3, compared with cells incubated with rapamycin or rapamycin and all-trans retinoic acid. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines, and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labeled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium.
CONCLUSIONS
Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. Incubation of patients' ex vivo expanded Treg cells with rapamycin and an RARA agonist induced expression of α4β7 and had suppressive and migratory activities in culture and in intestinal xenografts in mice. These cells might be developed for treatment of CD. ClinicalTrials.gov, Number: NCT03185000.
Identifiants
pubmed: 30710527
pii: S0016-5085(19)30048-4
doi: 10.1053/j.gastro.2019.01.025
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
FOXP3 protein, human
0
Forkhead Transcription Factors
0
Immunosuppressive Agents
0
Integrins
0
Organic Chemicals
0
RAR568
0
RARA protein, human
0
Retinoic Acid Receptor alpha
0
integrin alpha4beta7
0
L-Selectin
126880-86-2
Tretinoin
5688UTC01R
Sirolimus
W36ZG6FT64
Banques de données
ClinicalTrials.gov
['NCT03185000']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1775-1787Subventions
Organisme : British Heart Foundation
ID : RG/14/2/30616
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0901084
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N006445/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M003493/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802068
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.