Abstract
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.
| Original language | American English |
|---|---|
| Pages (from-to) | 1775-1787 |
| Number of pages | 13 |
| Journal | Gastroenterology |
| Volume | 156 |
| Issue number | 6 |
| DOIs | |
| State | Published - May 2019 |
Bibliographical note
Funding Information:Funding The authors acknowledge financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St Thomas’ NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. Additional support for some of the initial in vitro culture work and the ex vivo patient sample assays was provided by Litwin IBD Pioneers Funding Program at the Crohn's and Colitis Foundation (grant no. 504039), the Freemason's Grand Charity (grant no. SPG00268) and the Rosetrees Trust (A1219). Author contributions: Rimma Goldberg was responsible for study content and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analysis, and obtaining funding. Cristiano Scotta and Dianne Cooper contributed to acquisition of data and critical revision of manuscript for important intellectual content. Einat Nissim-Eliraz, Eilam Nir, and Scott Tasker contributed to acquisition of data. Peter M. Irving, Jeremy Sanderson, Paul Lavender, and Jonathan Corcoran contributed to acquisition of data, analysis and interpretation of data and critical revision of the manuscript for important intellectual content. Fowzia Ibrahim and Toby Prevost contributed a detailed review of the statistical methods. Nahum Y. Shpigel, Federica Marelli-Berg, and Giovanna Lombardi contributed to acquisition of data, critical revision of the manuscript for important intellectual content, and study supervision. Graham M. Lord defined the study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, obtaining funding, and overall study supervision.
Publisher Copyright:
© 2019 AGA Institute
Keywords
- Cell Therapy
- IBD
- Immune Regulation
- Tissue Engineering
