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Immunol."],"abstract":"<jats:p>Increasing evidence suggested that the islet amyloid polypeptide (IAPP) is an essential autoantigen in the pathogenesis of type 1 diabetes (T1D) in humans and non-obese diabetic (NOD) mice. A unique disulfide containing IAPP-derived peptide KS20 is one of the highly diabetogenic peptides in NOD mice. The KS20-reactive T cells, including prototypic pathogenic BDC5.2.9, accumulate in the pancreas of prediabetic and diabetic mice and contribute to disease development. We generated a monoclonal antibody (LD96.24) that interacts with IA<jats:sup>g7<\/jats:sup>-KS20 complexes with high affinity and specificity. LD96.24 recognized the IA<jats:sup>g7<\/jats:sup>-KS20 disulfide loop and blocked the interaction between IA<jats:sup>g7<\/jats:sup>-KS20 tetramers and cognate T cells but not other autoantigen-reactive T cells. The<jats:italic>in vivo<\/jats:italic>LD96.24 studies, at either early or late stages, drastically induced tolerance and delayed the onset of T1D disease in NOD mice by reducing the infiltration of not only IAPP-specific T cells but also chromogranin A and insulin-specific T cells in the pancreas, together with B cells and dendritic cells. LD96.24 can also significantly increase the ratio of Foxp3<jats:sup>+<\/jats:sup>regulatory T cells with Interferon-gamma-secreting effector T cells. Our data suggested the important role of disulfide-modified peptides in the development of T1D. Targeting the complexes of Major histocompatibility complex (MHC)\/disulfide modified antigens would influence the thiol redox balance and could be a novel immunotherapy for T1D.<\/jats:p>","DOI":"10.3389\/fimmu.2022.877022","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T14:25:37Z","timestamp":1660227937000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Tolerogenic Antibody Targeting Disulfide-Modified Autoantigen Effectively Prevents Type 1 Diabetes in NOD Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Wei","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronghui","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaodong","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.cmet.2019.11.017","article-title":"New Frontiers in the Treatment of Type 1 Diabetes","volume":"31","author":"Warshauer","year":"2020","journal-title":"Cell Metab"},{"key":"B2","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1007\/s13238-012-2077-7","article-title":"Recognition of Self and Altered Self by T Cells in Autoimmunity and Allergy","volume":"4","author":"Yin","year":"2013","journal-title":"Protein Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007765","article-title":"Do MHCII-Presented Neoantigens Drive Type 1 Diabetes and Other Autoimmune Diseases","volume":"2","author":"Marrack","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7382","article-title":"Oxidative Modifications in Tissue Pathology and Autoimmune Disease","volume":"29","author":"Yang","year":"2018","journal-title":"Antioxid Redox Signal"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716527115","article-title":"Et Al, C-Terminal Modification of the Insulin B:11-23 Peptide Creates Superagonists in Mouse and Human Type 1 Diabetes","volume":"115","author":"Wang","year":"2018","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1517862112","article-title":"N-Terminal Additions to the WE14 Peptide of Chromogranin A Create Strong Autoantigen Agonists in Type 1 Diabetes","volume":"112","author":"Jin","year":"2015","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e31823e46ef","article-title":"Further Evidence for Amyloid Deposition in Clinical Pancreatic Islet Grafts","volume":"93","author":"Westermark","year":"2012","journal-title":"Transplantation"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2016.10.007","article-title":"An Insulin-IAPP Hybrid Peptide is an Endogenous Antigen for CD4+T Cells in the non-Obese Diabetic Mouse","volume":"78","author":"Wiles","year":"2017","journal-title":"J Autoimmun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0288","article-title":"Islet Amyloid Polypeptide is a Target Antigen for Diabetogenic CD4+ T Cells","volume":"60","author":"Delong","year":"2011","journal-title":"Diabetes"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301480","article-title":"Cutting Edge: CD4+T Cells Reactive to an Islet Amyloid Polypeptide Peptide Accumulate in the Pancreas and Contribute to Disease Pathogenesis in Nonobese Diabetic Mice","volume":"191","author":"Baker","year":"2013","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.1991.tb01675.x","article-title":"Autoantibodies to Islet Amyloid Polypeptide in Diabetes","volume":"8","author":"Clark","year":"1991","journal-title":"Diabetes Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/BF02221685","article-title":"Detection of Autoantibodies Against Islet Amyloid Polypeptide in Human Serum. 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