Xin Chen1, M Cecilia Berin2, Virginia L Gillespie3, Hugh A Sampson2,4, David Dunkin1. 1. Division of Pediatric Gastroenterology and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States. 2. Division of Pediatric Allergy and Immunology, Precision Immunology Institute and Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States. 3. Center for Comparative Medicine and Surgery, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States. 4. DBV Technologies, LLC, Montrouge, France.
Abstract
Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-β in the suppression of colitis by epicutaneous immunotherapy (ET). Methods: RAG1-/- mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-β-producing Tregs were necessary, Foxp3-DTR, IL-10-/-, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTR mice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation. Results: ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTR mice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10-/- or CD4-dnTGFBRII mice. Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-β, could be a promising treatment for IBD.
Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-β in the suppression of colitis by epicutaneous immunotherapy (ET). Methods:RAG1-/- mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-β-producing Tregs were necessary, Foxp3-DTR, IL-10-/-, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTRmice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation. Results:ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTRmice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10-/- or CD4-dnTGFBRII mice. Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-β, could be a promising treatment for IBD.
Authors: Usriansyah Hadis; Benjamin Wahl; Olga Schulz; Matthias Hardtke-Wolenski; Angela Schippers; Norbert Wagner; Werner Müller; Tim Sparwasser; Reinhold Förster; Oliver Pabst Journal: Immunity Date: 2011-02-17 Impact factor: 31.745
Authors: Leonie Brockmann; Nicola Gagliani; Babett Steglich; Anastasios D Giannou; Jan Kempski; Penelope Pelczar; Maria Geffken; Bechara Mfarrej; Francis Huber; Johannes Herkel; Yisong Y Wan; Enric Esplugues; Manuela Battaglia; Christian F Krebs; Richard A Flavell; Samuel Huber Journal: J Immunol Date: 2016-12-21 Impact factor: 5.422
Authors: Xin Chen; Joanne Lai; Ying Song; Nan Yang; Sacha Gnjatic; Virginia Gillespie; William Hahn; Ezra Chefitz; Nanci Pittman; Jacqueline Jossen; Keith Benkov; Marla Dubinsky; Xiu-Min Li; David Dunkin Journal: Front Med (Lausanne) Date: 2021-11-29