{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:48:06Z","timestamp":1791460086927,"version":"4.3.4"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2019,3,1]],"date-time":"2019-03-01T00:00:00Z","timestamp":1551398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>MYMD-1 is a synthetic derivative of tobacco alkaloids, compounds that possess immunoregulatory properties and have been linked to the epidemiological observation that smoking reduces the odds of developing thyroid Abs and hypothyroidism. To assess the effect and mechanism(s) of the action of MYMD-1, we chose the NOD.H-2h4 mouse model of spontaneous thyroiditis. We began in vitro using T cells isolated from NOD.H-2h4 spleens and found that MYMD-1 suppressed TNF-\u03b1 production by CD4+ T cells in a dose-dependent manner. We then treated 58 NOD.H-2h4 mice for 12 wk with either unsupplemented water that contained (10 mice) or did not contain (16 mice) MYMD-1 (185 mg\/l) or water supplemented with sodium iodide (500 mg\/l) that contained (16 mice) or did not contain (16 mice) MYMD-1. Mice were bled at baseline and then every 2 wk until sacrifice. MYMD-1 decreased the incidence and severity (p &amp;lt; 0.001) of thyroiditis, as assessed by histopathology. Similarly, the number of CD3+ T cells and CD19+ B cells infiltrating the thyroid was dampened by MYMD-1, as assessed by flow cytometry. Interestingly, the subset of thyroidal CD3+CD4+Tbet+ROR\u03b3T\u2212 effector Th1 cells and the systemic levels of TNF-\u03b1 were decreased by MYMD-1. Serum thyroglobulin Abs decreased in the MYMD-1 group. Thyroid hormones did not differ among the four groups, whereas thyroid-stimulating hormone increased upon iodine supplementation but remained normal in MYMD-1\u2013treated mice. Overall, the study suggests that MYMD-1 ameliorates thyroiditis acting on specific lymphoid subsets. Further studies, including other models of autoimmunity, will confirm the potential clinical use of MYMD-1 as a novel immunometabolic regulator.<\/jats:p>","DOI":"10.4049\/jimmunol.1801238","type":"journal-article","created":{"date-parts":[[2019,1,23]],"date-time":"2019-01-23T20:58:19Z","timestamp":1548277099000},"page":"1350-1362","source":"Crossref","is-referenced-by-count":17,"title":["MYMD-1, a Novel Immunometabolic Regulator, Ameliorates Autoimmune Thyroiditis via Suppression of Th1 Responses and TNF-\u03b1 Release"],"prefix":"10.1093","volume":"202","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9213-8039","authenticated-orcid":false,"given":"Giulia","family":"Di Dalmazi","sequence":"first","affiliation":[{"name":"Division of Immunology, Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, MD 21205"},{"name":"Division of Endocrinology, Department of Medicine and Aging Sciences, G. D\u2019Annunzio University of Chieti-Pescara , Chieti 66100 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Chalan","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-6308","authenticated-orcid":false,"given":"Patrizio","family":"Caturegli","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, MD 21205"},{"name":"Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health , Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,1]]},"reference":[{"key":"2025030417560865500_r1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.autrev.2014.01.007","article-title":"Hashimoto thyroiditis: clinical and diagnostic criteria","volume":"13","author":"Caturegli","year":"2014","journal-title":"Autoimmun. 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Crohn\u2019s Colitis"},{"key":"2025030417560865500_r5","doi-asserted-by":"crossref","first-page":"417","DOI":"10.4049\/jimmunol.76.6.417","article-title":"Studies on organ specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extracts","volume":"76","author":"Rose","year":"1956","journal-title":"J. Immunol."},{"key":"2025030417560865500_r6","first-page":"546","article-title":"Experimental auto-immune thyroiditis in the rat","volume":"42","author":"Jones","year":"1961","journal-title":"Br. J. Exp. Pathol."},{"key":"2025030417560865500_r7","doi-asserted-by":"crossref","first-page":"3085","DOI":"10.1210\/en.2005-1130","article-title":"Induction of autoimmune thyroiditis and hypothyroidism by immunization of immunoactive T cell epitope of thyroid peroxidase","volume":"147","author":"Ng","year":"2006","journal-title":"Endocrinology"},{"key":"2025030417560865500_r8","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1084\/jem.178.3.793","article-title":"I-E+ nonobese diabetic mice develop insulitis and diabetes","volume":"178","author":"Podolin","year":"1993","journal-title":"J. Exp. Med."},{"key":"2025030417560865500_r9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ai.2014.11.001","article-title":"NOD.H-2h4 mice: an important and underutilized animal model of autoimmune thyroiditis and Sjogren\u2019s syndrome","volume":"126","author":"Braley-Mullen","year":"2015","journal-title":"Adv. Immunol."},{"key":"2025030417560865500_r10","doi-asserted-by":"crossref","first-page":"542","DOI":"10.3109\/08830185.2015.1065828","article-title":"Genes and environment as predisposing factors in autoimmunity: acceleration of spontaneous thyroiditis by dietary iodide in NOD.H2(h4) mice","volume":"34","author":"Kolypetri","year":"2015","journal-title":"Int. Rev. Immunol."},{"key":"2025030417560865500_r11","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1006\/cimm.1998.1446","article-title":"Both CD4(+) T cells and CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice","volume":"192","author":"Hutchings","year":"1999","journal-title":"Cell. Immunol."},{"key":"2025030417560865500_r12","doi-asserted-by":"crossref","first-page":"96","DOI":"10.4049\/jimmunol.1400561","article-title":"The thyroxine-containing thyroglobulin peptide (aa 2549-2560) is a target epitope in iodide-accelerated spontaneous autoimmune thyroiditis","volume":"193","author":"Kolypetri","year":"2014","journal-title":"J. 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Res."},{"key":"2025030417560865500_r33","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.4049\/jimmunol.169.7.3999","article-title":"Dual roles for IFN-gamma, but not for IL-4, in spontaneous autoimmune thyroiditis in NOD.H-2h4 mice","volume":"169","author":"Yu","year":"2002","journal-title":"J. Immunol."},{"key":"2025030417560865500_r34","doi-asserted-by":"crossref","first-page":"4448","DOI":"10.1210\/en.2011-1356","article-title":"Induction of autoimmune thyroiditis by depletion of CD4+CD25+ regulatory T cells in thyroiditis-resistant IL-17, but not interferon-gamma receptor, knockout nonobese diabetic-H2h4 mice","volume":"152","author":"Horie","year":"2011","journal-title":"Endocrinology"},{"key":"2025030417560865500_r35","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/nri802","article-title":"Development of anti-TNF therapy for rheumatoid arthritis","volume":"2","author":"Feldmann","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417560865500_r36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3109\/08916938909014703","article-title":"High potential to tumor necrosis factor alpha (TNF-alpha) production of thyroid infiltrating T lymphocytes in Hashimoto\u2019s thyroiditis: a peculiar feature of destructive thyroid autoimmunity","volume":"4","author":"Del Prete","year":"1989","journal-title":"Autoimmunity"},{"key":"2025030417560865500_r37","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1046\/j.1365-2567.2003.01547.x","article-title":"Tumour necrosis factor-alpha is a fundamental cytokine in autoimmune thyroid disease induced by thyroglobulin and lipopolysaccharide in interleukin-12 p40 deficient C57BL\/6 mice","volume":"108","author":"Zaccone","year":"2003","journal-title":"Immunology"},{"key":"2025030417560865500_r38","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1189\/jlb.0606402","article-title":"Decreasing TNF-alpha results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis","volume":"81","author":"Chen","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"2025030417560865500_r39","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1677\/joe.1.05887","article-title":"Autoinduction of tumor necrosis factor-alpha in FRTL-5 rat thyroid cells","volume":"187","author":"Mori","year":"2005","journal-title":"J. Endocrinol."},{"key":"2025030417560865500_r40","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nri803","article-title":"Effects of cigarette smoke on the immune system","volume":"2","author":"Sopori","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417560865500_r41","first-page":"479","article-title":"Nicotinic modulation of innate immune pathways via \u03b17 nicotinic acetylcholine receptor. [Published erratum appears in 2010 J. Neuroimmune Pharmacol. 5: 602\u2013603.]","volume-title":"J. 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Res."},{"key":"2025030417560865500_r45","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.expneurol.2010.09.020","article-title":"Attenuation of CNS inflammatory responses by nicotine involves \u03b17 and non-\u03b17 nicotinic receptors","volume":"227","author":"Hao","year":"2011","journal-title":"Exp. Neurol."},{"key":"2025030417560865500_r46","doi-asserted-by":"crossref","first-page":"e107979","DOI":"10.1371\/journal.pone.0107979","article-title":"The experimental autoimmune encephalomyelitis disease course is modulated by nicotine and other cigarette smoke components","volume":"9","author":"Gao","year":"2014","journal-title":"PLoS One"},{"key":"2025030417560865500_r47","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/art.24177","article-title":"Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice","volume":"60","author":"van Maanen","year":"2009","journal-title":"Arthritis Rheum."},{"key":"2025030417560865500_r48","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1002\/art.30219","article-title":"Nicotine-induced differential modulation of autoimmune arthritis in the Lewis rat involves changes in interleukin-17 and anti-cyclic citrullinated peptide antibodies","volume":"63","author":"Yu","year":"2011","journal-title":"Arthritis Rheum."},{"key":"2025030417560865500_r49","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1124\/jpet.300.3.876","article-title":"Nicotine reduces the incidence of type I diabetes in mice","volume":"300","author":"Mabley","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2025030417560865500_r50","doi-asserted-by":"crossref","first-page":"15895","DOI":"10.1038\/srep15895","article-title":"Dose-dependent protective effect of nicotine in a murine model of viral myocarditis induced by coxsackievirus B3. [Published erratum appears in 2015 Sci. Rep. 5: 17247.]","volume":"5","author":"Li-Sha","year":"2015","journal-title":"Sci. Rep."},{"key":"2025030417560865500_r51","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1038\/nm.3680","article-title":"Regulatory B cells are induced by gut microbiota-driven interleukin-1\u03b2 and interleukin-6 production","volume":"20","author":"Rosser","year":"2014","journal-title":"Nat. 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