{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:56:24Z","timestamp":1790618184636,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dairy Science and Technology Innovation Fund of the China Dairy Industry Association","award":["CDIAKCJJ-TP-2024-007"],"award-info":[{"award-number":["CDIAKCJJ-TP-2024-007"]}]},{"name":"National Science and Technology Major Project of China","award":["2019YFC1605002"],"award-info":[{"award-number":["2019YFC1605002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>To investigate the mechanism of oral immune tolerance induced by whey protein hydrolysates, this study utilized five industrially used proteases to hydrolyze whey protein and prepared the hydrolysates. An oral immune tolerance model was established using Balb\/c mice. The levels of specific IgG, IgE, and histamine in the serum of mice from the five hydrolysate-preventive groups were measured. The expression levels of genes and proteins associated with the MAPK signaling pathway in small intestinal mast cells were analyzed using qPCR and Western blot. The results demonstrated that the expression of JNK in the jejunum from the trypsin, bromelain, papain, Neutrase, and pepsin mouse groups was downregulated, which correlated with the alleviation of allergic responses. A moderate increase in ERK expression was accompanied by an expansion of Treg cells, thereby inducing oral immune tolerance. The process of oral immune tolerance was regulated by the MAPK signaling pathway. This study systematically elucidates the oral immune tolerance mechanisms of the five hydrolysates, and the conclusions will provide the guidance for the development of hypoallergenic infant formula.<\/jats:p>","DOI":"10.3390\/ijms27198637","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Mechanism of Whey Protein Hydrolysates with Oral Immunotolerance"],"prefix":"10.3390","volume":"27","author":[{"given":"Meng-Yue","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Engineering and Technology Research Center of Food Additives, College of Food and Health, Beijing Technology and Business University, Beijing 100048, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4300-0387","authenticated-orcid":false,"given":"Peng-Mei","family":"An","sequence":"additional","affiliation":[{"name":"Beijing Engineering and Technology Research Center of Food Additives, College of Food and Health, Beijing Technology and Business University, Beijing 100048, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Mao","sequence":"additional","affiliation":[{"name":"Beijing Engineering and Technology Research Center of Food Additives, College of Food and Health, Beijing Technology and Business University, Beijing 100048, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Wen-Xuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Beijing Engineering and Technology Research Center of Food Additives, College of Food and Health, Beijing Technology and Business University, Beijing 100048, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1473-2440","authenticated-orcid":false,"given":"Yan-Jun","family":"Cong","sequence":"additional","affiliation":[{"name":"Beijing Engineering and Technology Research Center of Food Additives, College of Food and Health, Beijing Technology and Business University, Beijing 100048, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.molimm.2022.05.005","article-title":"A comprehensive analysis of the components of common weed pollen and related allergens in patients with allergic diseases in southern China","volume":"147","author":"Xu","year":"2022","journal-title":"Mol. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4168\/aair.2011.3.2.67","article-title":"The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma","volume":"3","author":"Zheng","year":"2011","journal-title":"Allergy Asthma Immunol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Adedeji, A.A., Priyesh, P.V., and Odugbemi, A.A. (2024). The Magnitude and Impact of Food Allergens and the Potential of AI-Based Non-Destructive Testing Methods in Their Detection and Quantification. Foods, 13.","DOI":"10.3390\/foods13070994"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1016\/j.jaip.2023.06.062","article-title":"Exercise-Induced Allergic Reactions in Children Desensitized to Hen\u2019s Eggs and Cow\u2019s Milk by Oral Immunotherapy","volume":"11","author":"Tsuji","year":"2023","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13223-021-00583-w","article-title":"Canadian food ladders for dietary advancement in children with IgE-mediated allergy to milk and\/or egg","volume":"17","author":"Chomyn","year":"2021","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.2500\/aap.2019.40.4193","article-title":"A cross-sectional study of the prevalence of food allergies among children younger than ages 14 years in a Beijing urban region","volume":"40","author":"Sha","year":"2019","journal-title":"Allergy Asthma Proc."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kim, Y.H., Kim, Y.S., Park, Y., Kim, S.Y., Kim, K.W., Kim, H.S., and Sohn, M.H. (2020). Investigation of Basophil Activation Test for Diagnosing Milk and Egg Allergy in Younger Children. J. Clin. Med., 9.","DOI":"10.3390\/jcm9123942"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11882-024-01131-3","article-title":"The Natural History and Risk Factors for the Development of Food Allergies in Children and Adults","volume":"24","author":"Lee","year":"2024","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1016\/j.jaip.2024.04.057","article-title":"Dietary Advancement Therapy Using Milk and Egg Ladders Among Children with a History of Anaphylaxis","volume":"12","author":"Gallagher","year":"2024","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1016\/j.jaip.2024.06.016","article-title":"The Safety and Efficacy of Baked Egg and Milk Dietary Advancement Therapy: A Systematic Review and Meta-Analysis","volume":"12","author":"Anagnostou","year":"2024","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"104760","DOI":"10.1016\/j.jff.2021.104760","article-title":"Whey proteins processing and emergent derivatives: An insight perspective from constituents, bioactivities, functionalities to therapeutic applications","volume":"87","author":"Mehra","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1159\/000529305","article-title":"Component-Resolved Analyses for Diagnosis of Food Allergies in Infants and Young Children in Southern China","volume":"184","author":"An","year":"2023","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_13","unstructured":"B\u00f8gh, K.L., and Larsen, J.M. (2021). Agents of Change, Springer."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1111\/cea.13223","article-title":"Identification of peptides with tolerogenic potential in a hydrolysed whey-based infant formula","volume":"48","author":"Gouw","year":"2018","journal-title":"Clin. Exp. Allergy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9240046","DOI":"10.26599\/FSAP.2023.9240046","article-title":"Whey protein hydrolysates alleviated food allergy in mice by balancing the Th1\/Th2 pathway and increasing IgA antibody production","volume":"1","author":"Xinkun","year":"2023","journal-title":"Food Sci. Anim. Prod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164501","DOI":"10.1172\/JCI164501","article-title":"Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy","volume":"133","author":"LaHood","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9524075","DOI":"10.1155\/2018\/9524075","article-title":"Role of Histamine in Modulating the Immune Response and Inflammation","volume":"2018","author":"Branco","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"fyac056","DOI":"10.1093\/fqsafe\/fyac056","article-title":"Insight analysis of the cross-sensitization of multiple fish parvalbumins via the Th1\/Th2 immunological balance and cytokine release from the perspective of safe consumption of fish","volume":"6","author":"Wu","year":"2022","journal-title":"Food Qual. Saf."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/sj.cr.7290257","article-title":"Activation and signaling of the p38 MAP kinase pathway","volume":"15","author":"Zarubin","year":"2005","journal-title":"Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.jaci.2022.09.035","article-title":"Untargeted serum metabolomic analysis reveals a role for purinergic signaling in FPIES","volume":"151","author":"Chen","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_21","first-page":"4428","article-title":"FKBP11 protects intestinal epithelial cells against inflammation-induced apoptosis via the JNK-caspase pathway in Crohn\u2019s disease","volume":"18","author":"Wang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_22","first-page":"415","article-title":"Breakthroughs in the Fundamental Mechanistic Research on Regulatory T Cells and Their Clinical Translation Prospects","volume":"46","author":"Wang","year":"2026","journal-title":"J. Shanghai Jiaotong Univ. (Med. Sci.)"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.foodchem.2018.02.159","article-title":"Structural characteristics of low bitter and high umami protein hydrolysates prepared from bovine muscle and porcine plasma","volume":"257","author":"Fu","year":"2018","journal-title":"Food Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127254","DOI":"10.1016\/j.foodchem.2020.127254","article-title":"Properties of nano protein particle in solutions of myofibrillar protein extracted from giant squid (Dosidicusgigas)","volume":"330","author":"Niu","year":"2020","journal-title":"Food Chem."},{"key":"ref_25","unstructured":"Cong, Y.J., and Zhang, Q.Q. (2021). A Bovine Milk \u03b2-lactoglobulin T-cell Immunotolerant Hydrolysate, Its Preparation Method and Application. (202110567470.6), CN."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.3168\/jds.2021-20686","article-title":"Evaluation of allergenicity of cow milk treated with enzymatic hydrolysis through a mouse model of allergy","volume":"105","author":"Liang","year":"2022","journal-title":"J. Dairy Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.fshw.2022.09.011","article-title":"Enzymatic hydrolysis of silkworm pupa and its allergenicity evaluation by animal model with different immunization routes","volume":"12","author":"Dai","year":"2023","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1007\/s00217-021-03943-3","article-title":"Difference of egg ovalbumin sensitization between egg and duck eggs in BALB\/c mice","volume":"248","author":"Zhou","year":"2022","journal-title":"Eur. Food Res. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105487","DOI":"10.1016\/j.jff.2023.105487","article-title":"The immune-enhancing activity of egg white ovalbumin hydrolysate prepared with papain via MAPK signaling pathway in RAW 264.7 macrophages","volume":"103","author":"Cho","year":"2023","journal-title":"J. Funct. Foods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8637\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:58:56Z","timestamp":1790614736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,27]]},"references-count":29,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198637"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198637","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,27]]}}}