Gliadin Nanoparticles Induce Immune Tolerance to Gliadin in Mouse Models of Celiac Disease.
Administration, Intravenous
Animals
CD4-Positive T-Lymphocytes
Celiac Disease
/ blood
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Female
Gliadin
/ administration & dosage
Glutens
/ administration & dosage
HLA-DQ Antigens
/ genetics
Humans
Immune Tolerance
/ drug effects
Intestinal Mucosa
Leukocytes, Mononuclear
Mice
Mice, Transgenic
Nanoparticles
/ administration & dosage
Polyglactin 910
/ chemistry
Primary Cell Culture
Toxicity Tests, Acute
Gluten Sensitivity
Immunomodulation
Immunotherapy
Tolerogenic Vaccine
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
28
06
2019
revised:
26
01
2020
accepted:
27
01
2020
pubmed:
8
2
2020
medline:
21
10
2020
entrez:
8
2
2020
Statut:
ppublish
Résumé
Celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. We investigated the safety and efficacy of negatively charged 500-nm poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. Uptake of these nanoparticles by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease. We performed studies with C57BL/6; RAG1 TIMP-GLIA did not increase markers of maturation on cultured human dendritic cells or induce activation of T cells from patients with active or treated celiac disease. In the delayed-type hypersensitivity (model 1), the HLA-DQ8 transgenic (model 2), and the gliadin memory T-cell enteropathy (model 3) models of celiac disease, intravenous injections of TIMP-GLIA significantly decreased gliadin-specific T-cell proliferation (in models 1 and 2), inflammatory cytokine secretion (in models 1, 2, and 3), circulating gliadin-specific IgG/IgG2c (in models 1 and 2), ear swelling (in model 1), gluten-dependent enteropathy (in model 3), and body weight loss (in model 3). In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, had increased levels of FOXP3 and gene expression signatures associated with tolerance induction. In mice with gliadin sensitivity, injection of TIMP-GLIA nanoparticles induced unresponsiveness to gliadin and reduced markers of inflammation and enteropathy. This strategy might be developed for the treatment of celiac disease.
Sections du résumé
BACKGROUND & AIMS
Celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. We investigated the safety and efficacy of negatively charged 500-nm poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. Uptake of these nanoparticles by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease.
METHODS
We performed studies with C57BL/6; RAG1
RESULTS
TIMP-GLIA did not increase markers of maturation on cultured human dendritic cells or induce activation of T cells from patients with active or treated celiac disease. In the delayed-type hypersensitivity (model 1), the HLA-DQ8 transgenic (model 2), and the gliadin memory T-cell enteropathy (model 3) models of celiac disease, intravenous injections of TIMP-GLIA significantly decreased gliadin-specific T-cell proliferation (in models 1 and 2), inflammatory cytokine secretion (in models 1, 2, and 3), circulating gliadin-specific IgG/IgG2c (in models 1 and 2), ear swelling (in model 1), gluten-dependent enteropathy (in model 3), and body weight loss (in model 3). In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, had increased levels of FOXP3 and gene expression signatures associated with tolerance induction.
CONCLUSIONS
In mice with gliadin sensitivity, injection of TIMP-GLIA nanoparticles induced unresponsiveness to gliadin and reduced markers of inflammation and enteropathy. This strategy might be developed for the treatment of celiac disease.
Identifiants
pubmed: 32032584
pii: S0016-5085(20)30157-8
doi: 10.1053/j.gastro.2020.01.045
pmc: PMC7198359
mid: NIHMS1568962
pii:
doi:
Substances chimiques
HLA-DQ Antigens
0
HLA-DQ8 antigen
0
Polyglactin 910
34346-01-5
Glutens
8002-80-0
Gliadin
9007-90-3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1667-1681.e12Subventions
Organisme : NIBIB NIH HHS
ID : R01 EB013198
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS099334
Pays : United States
Informations de copyright
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
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