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Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice
David Dunkin1, M Cecilia Berin, Lucie Mondoulet
1*Division of Pediatric Gastroenterology, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; †Division of Pediatric Allergy and Immunology, Precision Immunology Institute, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; ‡DBV Technologies, Bagneux, France; §Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; ‖Department of Pathology, Columbia University Medical School, New York, New York; ¶National Veterinary School, Nantes, France; **Department of Comparative Pathology, Icahn School of Medicine at Mount Sinai, New York, New York; and ††Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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.
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