Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice.

Abstract

BACKGROUND:

Although inflammatory bowel disease (IBD) is a failure in maintaining tolerance to the intestinal microbiota, few studies have investigated the use of immunologic tolerance as a treatment approach for IBD. We hypothesized that induction of immune tolerance at a distal site could suppress intestinal inflammation through a process of bystander regulation.

METHODS:

Epicutaneous tolerance was induced by topical application of ovalbumin (OVA) using a Viaskin patch for 48 hours. In some experiments, a single feed of ovalbumin was used to drive epicutaneous tolerance-induced regulatory T cells (Tregs) to the intestine. The mechanism of tolerance induction was tested using neutralizing antibodies against TGF-β, IL-10, and Treg depletion using Foxp3-DTR mice. The capacity of skin-draining Tregs, or epicutaneous tolerance, to prevent or treat experimental IBD was tested using T-cell transfer colitis, dextran sodium sulfate (DSS) colitis, and ileitis in SAMP-YITFc mice. Weight loss, colonic inflammatory cytokines and histology were assessed.

RESULTS:

Epicutaneous exposure to ovalbumin induced systemic immune tolerance by a TGF-β-dependent, but IL-10 and iFoxp3 Treg-independent mechanism. Skin draining Tregs suppressed the development of colitis. Epicutaneous tolerance to a model antigen prevented intestinal inflammation in the dextran sodium sulfate and SAMP-YITFc models and importantly could halt disease in mice already experiencing weight loss in the T-cell transfer model of colitis. This was accompanied by a significant accumulation of LAP and Foxp3 Tregs in the colon.

CONCLUSIONS:

This is the first demonstration that epicutaneous tolerance to a model antigen can lead to bystander suppression of inflammation and prevention of disease progression in preclinical models of IBD.

• Authors: David Dunkin, M Cecilia Berin, Lucie Mondoulet, Steven Tobar, Garabet Yeretssian, Leticia Tordesillas, Alina Iuga, Thibaut Larcher, Virginia Gillespie, Pierre-Henri Benhamou, Jean-Frederic Colombel, Hugh A Sampson
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 23 Issue 11 Pg. 1972-1982 (11 2017) ISSN: 1536-4844 [Electronic] England
• PMID: 29019858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Forkhead Transcription Factors
• Interleukin-10
• Ovalbumin
• Dextran Sulfate

Topics

• Animals
• Colitis (chemically induced, immunology)
• Dextran Sulfate (administration & dosage)
• Disease Models, Animal
• Forkhead Transcription Factors (genetics)
• Ileitis (chemically induced, immunology)
• Immune Tolerance
• Inflammation (immunology, metabolism)
• Interleukin-10 (metabolism)
• Intestinal Mucosa (pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Ovalbumin (administration & dosage)
• T-Lymphocytes, Regulatory (immunology)