{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T15:28:42Z","timestamp":1785338922933,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2320-B-016-006-MY3"],"award-info":[{"award-number":["MOST 108-2320-B-016-006-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2314-B-385-001"],"award-info":[{"award-number":["MOST 108-2314-B-385-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of National Defense-Medical Affairs Bureau, Taiwan","award":["MAB-108-001"],"award-info":[{"award-number":["MAB-108-001"]}]},{"name":"Ministry of National Defense-Medical Affairs Bureau, Taiwan","award":["MAB-108-004"],"award-info":[{"award-number":["MAB-108-004"]}]},{"name":"Ministry of National Defense-Medical Affairs Bureau, Taiwan","award":["MAB-109-049"],"award-info":[{"award-number":["MAB-109-049"]}]},{"name":"Ministry of National Defense-Medical Affairs Bureau, Taiwan","award":["MND-MAB-C-11104-111014"],"award-info":[{"award-number":["MND-MAB-C-11104-111014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Type 1 diabetes mellitus (T1D) results from the destruction of insulin-producing \u03b2 cells in the islet of the pancreas by lymphocytes. Non-obese diabetic (NOD) mouse is an animal model frequently used for this disease. It has been considered that T1D is a T cell-mediated autoimmune disease. Both CD4+ and CD8+ T cells are highly responsible for the destruction of \u03b2 cells within the pancreatic islets of Langerhans. Previous studies have revealed that regulatory T (Treg) cells play a critical role in the homeostasis of the immune system as well as immune tolerance to autoantigens, thereby preventing autoimmunity. Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Previous reports have demonstrated that VPA treatment decreases the incidence and severity of collagen-induced arthritis and experimental autoimmune neuritis by increasing the population of Treg cells in these mouse disease models. Given the effect of VPA in the induction of Treg cells\u2019 population, we evaluated the therapeutic potential and the protective mechanism of VPA treatment in the suppression of graft autoimmune rejection and immune recurrence in syngeneic or allogenic islet transplantation mouse models. In our study, we found that the treatment of VPA increased the expression of forkhead box P3 (FOXP3), which is a critical transcription factor that controls Treg cells\u2019 development and function. Our data revealed that 400 mg\/kg VPA treatment in recipients effectively prolonged the survival of syngeneic and allogenic islet grafts. The percentage of Treg cells in splenocytes increased in VPA-treated recipients. We also proved that adoptive transfer of VPA-induced Tregs to the transplanted recipients effectively prolonged the survival of islet grafts. The results of this study provide evidence of the therapeutic potential and the underlying mechanism of VPA treatment in syngeneic islet transplantation for T1D. It also provides experimental evidence for cell therapy by adoptive transferring of in vitro VPA-induced Tregs for the suppression of autoimmune recurrence.<\/jats:p>","DOI":"10.3390\/ph14050475","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T12:19:57Z","timestamp":1621253997000},"page":"475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Valproic Acid Suppresses Autoimmune Recurrence and Allograft Rejection in Islet Transplantation through Induction of the Differentiation of Regulatory T Cells and Can Be Used in Cell Therapy for Type 1 Diabetes"],"prefix":"10.3390","volume":"14","author":[{"given":"Jeng-Rong","family":"Lin","sequence":"first","affiliation":[{"name":"Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shing-Hwa","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan"},{"name":"Department of General Surgery, En Chu Kong Hospital, New Taipei 23741, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hsiung","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, En Chu Kong Hospital, New Taipei 23741, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Wu","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Dentistry, National Defense Medical Center, Taipei 11490, Taiwan"},{"name":"Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Jie","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Pi","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huey-Kang","family":"Sytwu","sequence":"additional","affiliation":[{"name":"National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan 35053, Taiwan"},{"name":"Department of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4302-8196","authenticated-orcid":false,"given":"Gu-Jiun","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan"},{"name":"Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1016\/j.diabres.2003.09.015","article-title":"Prevention of type 1 diabetes: From the view point of beta cell damage","volume":"66","author":"Kawasaki","year":"2004","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.ecl.2010.05.011","article-title":"Epidemiology of type 1 diabetes","volume":"39","author":"Maahs","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1073\/pnas.93.3.1032","article-title":"A role of Hsp60 in autoimmune diabetes: Analysis in a transgenic model","volume":"93","author":"Birk","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1007\/s00125-009-1394-8","article-title":"Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes","volume":"52","author":"Devaraj","year":"2009","journal-title":"Diabetologia"},{"key":"ref_5","first-page":"91","article-title":"Virus-induced diabetes mellitus. II. Relationship between beta cell damage and hyperglycemia in mice infected with encephalomyocarditis virus","volume":"75","author":"Hayashi","year":"1974","journal-title":"Am. J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.autrev.2005.02.002","article-title":"NOD mice and autoimmunity","volume":"4","author":"Aoki","year":"2005","journal-title":"Autoimmun. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1586\/eci.10.68","article-title":"An update on the use of NOD mice to study autoimmune (Type 1) diabetes","volume":"6","author":"Chaparro","year":"2010","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jaut.2015.08.019","article-title":"The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes","volume":"66","author":"Pearson","year":"2016","journal-title":"J. Autoimmun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S1074-7613(00)80195-8","article-title":"B7\/CD28 Costimulation Is Essential for the Homeostasis of the CD4+CD25+ Immunoregulatory T Cells that Control Autoimmune Diabetes","volume":"12","author":"Salomon","year":"2000","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases","volume":"155","author":"Sakaguchi","year":"1995","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1172\/JCI25112","article-title":"Defective regulatory and effector T cell functions in patients with FOXP3 mutations","volume":"116","author":"Bacchetta","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/83713","article-title":"The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3","volume":"27","author":"Bennett","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"315ra189","DOI":"10.1126\/scitranslmed.aad4134","article-title":"Type 1 diabetes immunotherapy using polyclonal regulatory T cells","volume":"7","author":"Bluestone","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10991","DOI":"10.1038\/ncomms10991","article-title":"Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice","volume":"7","author":"Serr","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"695","DOI":"10.2165\/00023210-200216100-00004","article-title":"Pharmacological and Therapeutic Properties of Valproate: A Summary After 35 Years of Clinical Experience","volume":"16","author":"Perucca","year":"2002","journal-title":"CNS Drugs"},{"key":"ref_16","first-page":"435","article-title":"Pharmacodynamic properties of N-dipropylacetic acid","volume":"18","author":"Meunier","year":"1963","journal-title":"Therapie"},{"key":"ref_17","first-page":"385","article-title":"On the propyl derivatives and decomposition products of ethylacetoacetate","volume":"3","author":"BS","year":"1882","journal-title":"Am. Chem. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1124\/pr.111.005512","article-title":"Therapeutic potential of mood stabilizers lithium and valproic acid: Beyond bipolar disorder","volume":"65","author":"Chiu","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s11010-011-1085-x","article-title":"VPA inhibits breast cancer cell migration by specifically targeting HDAC2 and down-regulating Survivin","volume":"361","author":"Zhang","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1007\/s10753-017-0574-9","article-title":"Anti-inflammatory Effects of Valproic Acid in a Rat Model of Renal Ischemia\/Reperfusion Injury: Alteration in Cytokine Profile","volume":"40","author":"Amirzargar","year":"2017","journal-title":"Inflammation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"28656","DOI":"10.1074\/jbc.M112.356584","article-title":"The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis","volume":"287","author":"Lv","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.neuroscience.2012.07.013","article-title":"Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats","volume":"221","author":"Zhang","year":"2012","journal-title":"Neuroscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.yexmp.2009.06.003","article-title":"Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis","volume":"87","author":"Saouaf","year":"2009","journal-title":"Exp. Mol. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.2522\/ptj.20080020","article-title":"Epidemiology of diabetes and diabetes-related complications","volume":"88","author":"Deshpande","year":"2008","journal-title":"Phys. Ther."},{"key":"ref_25","first-page":"Ra130","article-title":"Diabetes mellitus: Complications and therapeutics","volume":"12","author":"Tripathi","year":"2006","journal-title":"Med. Sci. Monit."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/03007995.2018.1470970","article-title":"Patient preferences for diabetes-related complications in Taiwan","volume":"35","author":"Lin","year":"2019","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.arcmed.2005.03.014","article-title":"Islet transplantation: Progress and challenge","volume":"36","author":"Gaglia","year":"2005","journal-title":"Arch. Med. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1080\/19382014.2018.1428511","article-title":"The journey of islet cell transplantation and future development","volume":"10","author":"Gamble","year":"2018","journal-title":"Islets"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/01.mpa.0000203961.16630.2f","article-title":"Prospective and Challenges of Islet Transplantation for the Therapy of Autoimmune Diabetes","volume":"32","author":"Balamurugan","year":"2006","journal-title":"Pancreas"},{"key":"ref_30","first-page":"132","article-title":"Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases","volume":"53","author":"Sibley","year":"1985","journal-title":"Lab. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1056\/NEJM199609193351205","article-title":"Recurrence of autoimmune diabetes mellitus in recipients of cadaveric pancreatic grafts","volume":"335","author":"Tyden","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_32","first-page":"421","article-title":"Valproic acid-induced acute pancreatitis","volume":"61","author":"Jain","year":"2019","journal-title":"Indian J. Psychol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1111\/bcpt.13049","article-title":"Risk Factors for Valproic Acid-induced Hyperammonaemia in Chinese Paediatric Patients with Epilepsy","volume":"123","author":"Zhu","year":"2018","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/gt.2013.78","article-title":"Modulation of Treg function improves adenovirus vector-mediated gene expression in the airway","volume":"21","author":"Nagai","year":"2014","journal-title":"Gene Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1093\/intimm\/dxn002","article-title":"STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25- effector T cells","volume":"20","author":"Passerini","year":"2008","journal-title":"Int. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3871","DOI":"10.1128\/MCB.18.7.3871","article-title":"Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation","volume":"18","author":"Onishi","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/j.1399-0012.2005.00378.x","article-title":"Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004","volume":"19","author":"Gruessner","year":"2005","journal-title":"Clin. Transplant."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4055","DOI":"10.1007\/s00018-008-8521-4","article-title":"Valproic acid attenuates inflammation in experimental autoimmune neuritis","volume":"65","author":"Zhang","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1097\/TP.0000000000001197","article-title":"Modulation of Donor-Specific Antibody Production after Organ Transplantation by Valproic Acid: A Histone Deacetylase Inhibitor","volume":"100","author":"Ye","year":"2016","journal-title":"Transplantation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.clinbiochem.2013.06.012","article-title":"Adverse drug reactions induced by valproic acid","volume":"46","author":"Nanau","year":"2013","journal-title":"Clin. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.seizure.2012.05.001","article-title":"Valproate sodium enhances body weight gain in patients with childhood epilepsy: A pathogenic mechanisms and open-label clinical trial of behavior therapy","volume":"21","author":"Kanemura","year":"2012","journal-title":"Seizure"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/nri954","article-title":"The lineage decisions of helper T cells","volume":"2","author":"Murphy","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.immuni.2006.01.001","article-title":"TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells","volume":"24","author":"Veldhoen","year":"2006","journal-title":"Immunity."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s12985-016-0626-z","article-title":"Valproic acid ameliorates coxsackievirus-B3-induced viral myocarditis by modulating Th17\/Treg imbalance","volume":"13","author":"Jin","year":"2016","journal-title":"Virol. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s11892-017-0916-x","article-title":"The Role of Epigenetics in Type 1 Diabetes","volume":"17","author":"Jerram","year":"2017","journal-title":"Curr. Diab. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"San Jose-Eneriz, E., Gimenez-Camino, N., Agirre, X., and Prosper, F. (2019). HDAC Inhibitors in Acute Myeloid Leukemia. Cancers, 11.","DOI":"10.3390\/cancers11111794"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1038\/cdd.2017.71","article-title":"It is a differentiation game: STAT5 in a new role","volume":"24","author":"Maurer","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1210\/endo-77-6-1061","article-title":"Reversal of the effect of pinealectomy in female rats by multiple isogeneic pineal transplants","volume":"77","author":"Gittes","year":"1965","journal-title":"Endocrinology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1096\/fj.201900927RR","article-title":"Butyrate prevents valproate-induced liver injury: In vitro and in vivo evidence","volume":"34","author":"Pirozzi","year":"2020","journal-title":"FASEB J"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"343","DOI":"10.2174\/1381612825666190329145428","article-title":"Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update","volume":"25","author":"Guo","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2698","DOI":"10.1016\/S0041-1345(02)03380-8","article-title":"Effects of multiple site implantation on islet transplantation","volume":"34","author":"Juang","year":"2002","journal-title":"Transplant. Proc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"114641","DOI":"10.1016\/j.taap.2019.114641","article-title":"Adoptive transfer of DMSO-induced regulatory T cells exhibits a similar preventive effect compared to an in vivo DMSO treatment for chemical-induced experimental encapsulating peritoneal sclerosis in mice","volume":"378","author":"Lin","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/5\/475\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:02:49Z","timestamp":1760162569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/5\/475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,17]]},"references-count":52,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ph14050475"],"URL":"https:\/\/doi.org\/10.3390\/ph14050475","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,17]]}}}