{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:58:27Z","timestamp":1790402307590,"version":"4.1.0"},"reference-count":29,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>The pathogenesis of thyroiditis caused by immune-checkpoint inhibitors (ICIs) such as antiprogrammed death receptor-1 (PD-1) and anticytotoxic T lymphocyte antigen-4 (CTLA-4) is incompletely understood. To gain mechanistic insights, we developed a mouse model of ICI-related thyroiditis and assessed the clinical, hormonal, and cytokine profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Forty NOD-H2\n                      <jats:sup>h4<\/jats:sup>\n                      mice, 112 days old at the start of the experiments, were divided into two sequential cohorts. In the first one (No.\u2009=\u200921), mice were injected with both anti-PD-1 and anti-CTLA-4 checkpoint inhibitors while drinking either regular water or iodine-supplemented water. In the second cohort (No.\u2009=\u200919), mice were injected with either anti-PD-1 or anti-CTLA-4 while drinking iodine-supplemented water. Mice were sacrificed two months after the initial injection to collect thyroid gland for histopathology (to assess thyroiditis severity) and flow cytometry (to identify immune cell subsets and tissue-resident memory T cell markers). Mice were also studied before sacrifice to determine thyroid area and structure (by ultrasound), thyroid function (serum total thyroxine, thyrotropin, thyroid antibodies), and cytokine profile (by bead-based Luminex technology).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Thyroiditis was more severe upon PD-1 than CTLA-4 blockade (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.01) and significantly correlated with the number of CD45\n                      <jats:sup>+<\/jats:sup>\n                      cells infiltrating the thyroid (cumulative odds ratio [OR] 1.2 [95% confidence interval, CI 1.1\u20131.3],\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.001, that is 20% greater odds of a higher severity score for every 170-unit increase in CD45 infiltrating cells). Thyroiditis was instead more prevalent (100% vs. 63%,\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.01) in the anti-CTLA-4 mice, which also showed a larger thyroid area (17\u2009\u00b1\u20098.2\u2009mm) than those treated with anti-PD-1 (11\u2009\u00b1\u20094.2\u2009mm) and controls (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Serum IL-6 was markedly increased upon PD-1 blockade (40\u2009pg\/mL at baseline, 198\u2009pg\/mL on day 172), an increase not seen in the anti-CTLA-4 group (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.01). IL-6 mirrored thyroiditis severity, with highest serum values found in greatest histopathology scores (cumulative OR 1.1 [CI 1.02\u20131.15],\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.009). GM-CSF and MIP1\u03b2 increased more in the anti-CTLA-4 group (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.001 for both), whereas the other cytokines did not differ among the treatment groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>The study reports a mouse model of thyroiditis induced by PD-1 blockade and, comparing it to the anti-CTLA-4 model, uncovers distinctive histopathological, sonographic, hormonal, and immunological features, offering biomarkers, such as serum IL-6, that could be used in the clinical setting.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2021.0165","type":"journal-article","created":{"date-parts":[[2021,10,2]],"date-time":"2021-10-02T01:37:36Z","timestamp":1633138656000},"page":"1839-1849","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":23,"title":["Distinct Cytokine Signatures in Thyroiditis Induced by PD-1 or CTLA-4 Blockade: Insights from a New Mouse Model"],"prefix":"10.1177","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2982-3153","authenticated-orcid":false,"given":"Silvia","family":"Ippolito","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Medicine and Surgery, Ospedale Di Circolo - Insubria University, Varese, Italy."},{"name":"Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9213-8039","authenticated-orcid":false,"given":"Giulia","family":"Di Dalmazi","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA."},{"name":"Endocrine Unit, Department of Medicine and Aging Science, Center for Advanced Studies and Technology (CAST) - G. D'Annunzio University, Chieti-Pescara, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Pani","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Sabini","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA."}],"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 School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-017-0778-8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31200"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009-0417"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801238"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-1165"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13249"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqab144"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/105072503322021070"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4075"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.13028"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00813"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-0736-7"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2016.0092"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3010641"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2744"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201305"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402711"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8097338"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4800(03)80002-3"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(199906)29:06<1933::AID-IMMU1933>3.0.CO;2-3"},{"key":"e_1_3_4_22_2","first-page":"630","article-title":"[Measurement of IL-12 and IL-18 in sera of patients with autoimmune thyroid disease]","volume":"22","author":"Zhang JA","year":"2006","unstructured":"Zhang JA, , Zhang J, , Xu L, , Mar H, , Wu XY. 2006. [Measurement of IL-12 and IL-18 in sera of patients with autoimmune thyroid disease]. 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