{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:49:52Z","timestamp":1781246992485,"version":"3.54.1"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008871","name":"Juvenile Diabetes Research Foundation","doi-asserted-by":"publisher","award":["2-SRA-2016-303-S-B"],"award-info":[{"award-number":["2-SRA-2016-303-S-B"]}],"id":[{"id":"10.13039\/100008871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR001881."],"award-info":[{"award-number":["UL1TR001881."]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We have proposed that antigen-specific immunotherapies (ASIs) for autoimmune diseases could be enhanced by administering target cell antigen epitopes (determinants) that are immunogenic but ignored by autoreactive T cells because these determinants may have large pools of na\u00efve cognate T cells available for priming towards regulatory responses. Here, we identified an immunogenic preproinsulin determinant (PPIL4-20) that was ignored by autoimmune responses in type 1 diabetes (T1D)-prone NOD mice. The size of the PPIL4-20-specific splenic naive T cell pool gradually increased from 2\u201312 weeks in age and remained stable thereafter, while that of the major target determinant insulin B-chain9-23 decreased greatly after 12 weeks in age, presumably due to recruitment into the autoimmune response. In 15\u201316 week old mice, insulin B-chain9-23\/alum immunization induced modest-low level of splenic T cell IL-10 and IL-4 responses, little or no spreading of these responses, and boosted IFN\u03b3 responses to itself and other autoantigens. In contrast, PPIL4-20\/alum treatment induced robust IL-10 and IL-4 responses, which spread to other autoantigens and increased the frequency of splenic IL-10-secreting Treg and Tr-1-like cells, without boosting IFN\u03b3 responses to \u00df-cell autoantigens. In newly diabetic NOD mice, PPIL4-20, but not insulin B-chain9-23 administered intraperitoneally (with alum) or intradermally (as soluble antigen) supplemented with oral GABA induced long-term disease remission. We discuss the potential of personalized ASIs that are based on an individual\u2019s na\u00efve autoantigen-reactive T cell pools and the use of HLA-appropriate ignored autoantigen determinants to safely enhance the efficacy of ASIs.<\/jats:p>","DOI":"10.3390\/cells11071081","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T12:20:25Z","timestamp":1648038025000},"page":"1081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Designing Personalized Antigen-Specific Immunotherapies for Autoimmune Diseases\u2014The Case for Using Ignored Target Cell Antigen Determinants"],"prefix":"10.3390","volume":"11","author":[{"given":"Jide","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, UCLA School of Medicine, University of California, Los Angeles, CA 90095-1735, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, UCLA School of Medicine, University of California, Los Angeles, CA 90095-1735, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, UCLA School of Medicine, University of California, Los Angeles, CA 90095-1735, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.2337\/db09-0451","article-title":"Antigen-based therapy for the treatment of type 1 diabetes","volume":"58","author":"Tian","year":"2009","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S2213-8587(18)30109-8","article-title":"Antigen-based immune modulation therapy for type 1 diabetes: The era of precision medicine","volume":"7","author":"Roep","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/imcb.12439","article-title":"A century later, still fighting back: Antigen-specific immunotherapies for type 1 diabetes","volume":"99","author":"Barneda","year":"2021","journal-title":"Immunol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00125-016-4122-1","article-title":"GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: Findings from a Bayesian meta-analysis","volume":"60","author":"Beam","year":"2017","journal-title":"Diabetologia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1007\/s00125-020-05227-z","article-title":"Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes","volume":"63","author":"Hannelius","year":"2020","journal-title":"Diabetologia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.2337\/dc21-0318","article-title":"Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial","volume":"44","author":"Ludvigsson","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.4049\/jimmunol.1102661","article-title":"The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude","volume":"188","author":"Jenkins","year":"2012","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.immuni.2007.07.007","article-title":"Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude","volume":"27","author":"Moon","year":"2007","journal-title":"Immunity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.4049\/jimmunol.175.3.1991","article-title":"Antigen-based therapies using ignored determinants of beta cell antigens can more effectively inhibit late-stage autoimmune disease in diabetes-prone mice","volume":"175","author":"Olcott","year":"2005","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature22991","article-title":"An immunogenic personal neoantigen vaccine for patients with melanoma","volume":"547","author":"Ott","year":"2017","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s41591-020-01206-4","article-title":"Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma","volume":"27","author":"Hu","year":"2021","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.4049\/jimmunol.161.10.5399","article-title":"Attenuation of inducible Th2 immunity with autoimmune disease progression","volume":"161","author":"Tian","year":"1998","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5463879","DOI":"10.1155\/2018\/5463879","article-title":"Immature Dendritic Cell Therapy Confers Durable Immune Modulation in an Antigen-Dependent and Antigen-Independent Manner in Nonobese Diabetic Mice","volume":"2018","author":"Lo","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.4049\/jimmunol.152.5.2279","article-title":"Self peptides isolated from MHC glycoproteins of non-obese diabetic mice","volume":"152","author":"Reich","year":"1994","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1084\/jem.185.6.1013","article-title":"A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB\/H mice","volume":"185","author":"Harrison","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1126\/science.288.5465.505","article-title":"A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes","volume":"288","author":"Corper","year":"2000","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/eji.1830250430","article-title":"Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice","volume":"25","author":"Daniel","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16729","DOI":"10.1073\/pnas.1113954108","article-title":"Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse","volume":"108","author":"Crawford","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1172\/JCI8525","article-title":"A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin","volume":"107","author":"Alleva","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/366069a0","article-title":"Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes","volume":"366","author":"Kaufman","year":"1993","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1073\/pnas.88.8.3088","article-title":"Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein","volume":"88","author":"Elias","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3942","DOI":"10.4049\/jimmunol.162.7.3942","article-title":"Adjuvant-guided type-1 and type-2 immunity: Infectious\/noninfectious dichotomy defines the class of response","volume":"162","author":"Yip","year":"1999","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1126\/science.271.5256.1728","article-title":"Induction of TH1 and TH2 immunity in neonatal mice","volume":"271","author":"Forsthuber","year":"1996","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/nm1296-1348","article-title":"Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice","volume":"2","author":"Tian","year":"1996","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.2337\/db13-1385","article-title":"Combined therapy with GABA and proinsulin\/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting beta-cell replication in newly diabetic NOD mice","volume":"63","author":"Tian","year":"2014","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/cei.12687","article-title":"Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model","volume":"182","author":"Gibson","year":"2015","journal-title":"Clin. Exp. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"465","DOI":"10.3109\/08916934.2011.571223","article-title":"Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis","volume":"44","author":"Tian","year":"2011","journal-title":"Autoimmunity"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11","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":"ref_29","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1084\/jem.186.12.2039","article-title":"Determinant spreading of T helper cell 2 (Th2) responses to pancreatic islet autoantigens","volume":"186","author":"Tian","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6564","DOI":"10.4049\/jimmunol.169.11.6564","article-title":"Antigen-based immunotherapy drives the precocious development of autoimmunity","volume":"169","author":"Tian","year":"2002","journal-title":"J Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1084\/jem.20071878","article-title":"Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production","volume":"205","author":"Jain","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1007\/s00125-002-0897-3","article-title":"Heat shock protein therapy fails to prevent diabetes in NOD mice","volume":"45","author":"Bowman","year":"2002","journal-title":"Diabetologia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5298","DOI":"10.4049\/jimmunol.173.8.5298","article-title":"Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model","volume":"173","author":"Tian","year":"2004","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.2337\/db13-0931","article-title":"gamma-Aminobutyric acid regulates both the survival and replication of human beta-cells","volume":"62","author":"Tian","year":"2013","journal-title":"Diabetes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11692","DOI":"10.1073\/pnas.1102715108","article-title":"GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes","volume":"108","author":"Soltani","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4197","DOI":"10.2337\/db14-0153","article-title":"GABA promotes human beta-cell proliferation and modulates glucose homeostasis","volume":"63","author":"Purwana","year":"2014","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1097\/TP.0b013e31829c24be","article-title":"GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone","volume":"96","author":"Glinka","year":"2013","journal-title":"Transplantation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1600-065X.1998.tb01214.x","article-title":"Infectious Th1 and Th2 autoimmunity in diabetes-prone mice","volume":"164","author":"Tian","year":"1998","journal-title":"Immunol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/ni1077","article-title":"\u2018Educated\u2019 dendritic cells act as messengers from memory to naive T helper cells","volume":"5","author":"Alpan","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.cellimm.2003.08.007","article-title":"Memory and effector T cells modulate subsequently primed immune responses to unrelated antigens","volume":"224","author":"Tian","year":"2003","journal-title":"Cell. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tian, J., Dang, H., and Kaufman, D.L. (2011). Combining antigen-based therapy with GABA treatment synergistically prolongs survival of transplanted ss-cells in diabetic NOD mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025337"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"498","DOI":"10.4049\/immunohorizons.1900019","article-title":"Homotaurine treatment enhances CD4+ and CD8+ Treg responses and synergizes with low-dose anti-CD3 to enhance diabetes remission in type 1 diabetic mice","volume":"3","author":"Tian","year":"2019","journal-title":"ImmunoHorizons"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tian, J., Dang, H.N., Yong, J., Chui, W.-S., Dizon, M.P.G., Yaw, C.K.Y., and Kaufman, D.L. (2011). Oral treatment with gamma-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025338"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0165-5728(98)00264-1","article-title":"GABA(A) receptors mediate inhibition of T cell responses","volume":"96","author":"Tian","year":"1999","journal-title":"J. Neuroimmunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nri3020","article-title":"Interrogating the repertoire: Broadening the scope of peptide-MHC multimer analysis","volume":"11","author":"Davis","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1084\/jem.20130555","article-title":"Proteome-wide analysis of HIV-specific naive and memory CD4(+) T cells in unexposed blood donors","volume":"211","author":"Campion","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1084\/jem.190.5.705","article-title":"High frequencies of naive Melan-A\/MART-1-specific CD8(+) T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals","volume":"190","author":"Pittet","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1038\/s41590-021-01073-2","article-title":"High-throughput and high-dimensional single-cell analysis of antigen-specific CD8(+) T cells","volume":"22","author":"Ma","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"eabf5835","DOI":"10.1126\/sciadv.abf5835","article-title":"A framework for highly multiplexed dextramer mapping and prediction of T cell receptor sequences to antigen specificity","volume":"7","author":"Zhang","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/sji.12344","article-title":"Major Histocompatibility Complex Class II Dextramers: New Tools for the Detection of antigen-Specific, CD4 T Cells in Basic and Clinical Research","volume":"82","author":"Massilamany","year":"2015","journal-title":"Scand. J. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/7\/1081\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:41:48Z","timestamp":1760136108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/7\/1081"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,23]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["cells11071081"],"URL":"https:\/\/doi.org\/10.3390\/cells11071081","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,23]]}}}