Oral Immunotherapy with Egg Peptides Induces Innate and Adaptive Tolerogenic Responses

• Published in: Molecular nutrition & food research Vol. 63; no. 17; pp. e1900144 - n/a
• Main Authors: Lozano‐Ojalvo, Daniel, Martínez‐Blanco, Mónica, Pérez‐Rodríguez, Leticia, Molina, Elena, López‐Fandiño, Rosina
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.09.2019
• Subjects: Administration, Oral; Aldehyde dehydrogenase; aldehyde dehydrogenases; Aldehydes; Animals; Bone marrow; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell culture; Coculture Techniques; Conditioning; Cytokines; Dendritic cells; Dendritic Cells - immunology; Desensitization; Egg Hypersensitivity - immunology; Egg Proteins - immunology; Epithelial cells; Epithelial Cells - immunology; Female; Food allergies; Forkhead Transcription Factors - metabolism; Foxp3 protein; Foxp3+ RORγt+ T cells; Immune system; Immune Tolerance - immunology; Immunotherapy; Immunotherapy - methods; Incubation; Inflammation; Innate immunity; Interferon; intestinal epithelial cells; Intestine; Intestines - cytology; Intestines - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred BALB C; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Oral administration; Ovalbumin; Ovalbumin - administration & dosage; Ovalbumin - immunology; Pepsin; Pepsin A - chemistry; Pepsin A - immunology; peptide immunotherapy; Peptides; Protein Hydrolysates - immunology; Protein Hydrolysates - pharmacology; T-Lymphocytes, Helper-Inducer - immunology; Thymic stromal lymphopoietin; Transforming growth factor-b1; intestinal epithelial cells; aldehyde dehydrogenases; Foxp3+ RORγt+ T cells; dendritic cells; peptide immunotherapy
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201900144

Scope The mechanism through which peptide‐based immunotherapy provides effective desensitization toward food allergy is investigated. Methods and results Ex vivo experiments are conducted with intestinal epithelial cells (IECs), dendritic cells (DCs), and T cells from mice sensitized to egg white (EW) and either left untreated or tolerized by the oral administration of a hydrolysate of ovalbumin with pepsin (OP). IECs from EW‐sensitized mice upregulate Il33 and Tslp to a higher extent than those from tolerized mice and induce bone marrow (BM)‐DCs to express Tnfsf4 and produce pro‐inflammatory cytokines. On the other hand, incubation with OP upregulates Aldh1a1 in IEC cultures and BM‐DCs conditioned with supernatants of OP‐pulsed IECs also overexpress Aldh1a2 and Tgfb1. DCs from tolerized mice, in co‐culture with CD4+ T cells from sensitized mice, reduce the secretion of IL‐5, IFN‐γ, and IL‐17, following stimulation with EW, to a level similar than DCs from sham‐sensitized mice. Furthermore, incubation with OP of DCs and CD4+ T cells, regardless of the mouse sentitization status, promotes the secretion of TGF‐β and the generation of Foxp3+ RORγt+ cells. Conclusion OP induces the expression of aldehyde dehydrogenase enzymes in cells of the innate immune system and the development of Foxp3+ RORγt+ T cells. Intestinal epithelial cells from food allergic mice induce pro‐inflammatory properties in dendritic cells that promote the development of Th2, Th1, and Th17 responses on T cells. Peptide immunotherapy upregulates vitamin A metabolism by inducing the expression of aldehyde dehydrogenases on intestinal epithelial cells and dendritic cells, promotes the expansion of T cells that simultaneously express Foxp3 and RORγt, and attenuates Th2, Th1, and Th17 responses on T cells from allergic mice.