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Akad\u00e9mia","doi-asserted-by":"publisher","award":["LP\u20102021\u201014"],"award-info":[{"award-number":["LP\u20102021\u201014"]}],"id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICI), such as anti\u2010PD\u20101 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T\u2010cells against tumours. However, enhanced T\u2010cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI\u2010induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD\u20101 inhibition on cardiac function and explore the molecular mechanisms of ICI\u2010induced cardiotoxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>C57BL6\/J and BALB\/c mice were treated with isotype control or anti\u2010PD\u20101 antibody.<\/jats:p>\n                    <jats:p>Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT\u2010PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow\u2010up experiments, anti\u2010CD4 and anti\u2010IL\u201017A antibodies were used along with PD\u20101 blockade in C57BL\/6J mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Anti\u2010PD\u20101 treatment led to cardiac dysfunction and left ventricular dilation in C57BL\/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD\u20101 inhibition resulted in enhanced thymic inflammatory signalling, where\n                      <jats:italic>Il17a<\/jats:italic>\n                      increased most prominently. In BALB\/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL\u201017A prevented anti\u2010PD\u20101\u2010induced cardiac dysfunction in C57BL6\/J mice. Comparing myocardial transcriptomic changes in C57BL\/6J and BALB\/c mice, differentially regulated genes (\n                      <jats:italic>Dmd<\/jats:italic>\n                      ,\n                      <jats:italic>Ass1<\/jats:italic>\n                      ,\n                      <jats:italic>Chrm2<\/jats:italic>\n                      ,\n                      <jats:italic>Nfkbia<\/jats:italic>\n                      ,\n                      <jats:italic>Stat3<\/jats:italic>\n                      ,\n                      <jats:italic>Gsk3b<\/jats:italic>\n                      ,\n                      <jats:italic>Cxcl9<\/jats:italic>\n                      ,\n                      <jats:italic>Fxyd2<\/jats:italic>\n                      , and\n                      <jats:italic>Ldb3<\/jats:italic>\n                      ) were revealed, related to cardiac structure, signalling, and inflammation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PD\u20101 blockade induces cardiac dysfunction in mice with increased IL\u201017 signalling in the thymus. Pharmacological inhibition of IL\u201017A treatment prevents ICI\u2010induced cardiac dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15984","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T14:14:45Z","timestamp":1668089685000},"page":"740-761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Characterization of immune checkpoint inhibitor\u2010induced cardiotoxicity reveals interleukin\u201017A as a driver of cardiac dysfunction after anti\u2010PD\u20101 treatment"],"prefix":"10.1111","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1972-2065","authenticated-orcid":false,"given":"Tam\u00e1s G.","family":"Gergely","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary"},{"name":"HCEMM\u2010SE Cardiometabolic Immunology Research Group Semmelweis University Budapest Hungary"},{"name":"MTA\u2010SE Momentum Cardio\u2010Oncology and Cardioimmunology Research Group Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"Kucsera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary"},{"name":"HCEMM\u2010SE Cardiometabolic Immunology Research Group Semmelweis University Budapest Hungary"},{"name":"MTA\u2010SE Momentum Cardio\u2010Oncology and Cardioimmunology Research Group Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikt\u00f3ria E.","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary"},{"name":"HCEMM\u2010SE Cardiometabolic Immunology Research Group Semmelweis University Budapest Hungary"},{"name":"MTA\u2010SE Momentum Cardio\u2010Oncology and Cardioimmunology Research Group Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary"},{"name":"HCEMM\u2010SE Cardiometabolic Immunology Research Group Semmelweis University Budapest Hungary"},{"name":"MTA\u2010SE Momentum Cardio\u2010Oncology and Cardioimmunology Research Group Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil V.","family":"Sayour","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary"},{"name":"HCEMM\u2010SE Cardiometabolic Immunology Research Group Semmelweis University Budapest Hungary"},{"name":"MTA\u2010SE Momentum Cardio\u2010Oncology and Cardioimmunology Research Group Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zs\u00f3fia D.","family":"Drobni","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mih\u00e1ly","family":"Ruppert","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal\u00e1zs","family":"Petrovich","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-0426","authenticated-orcid":false,"given":"Bence","family":"\u00c1gg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest 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Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9va","family":"P\u00e1llinger","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell\u2010 and Immunobiology Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edit I.","family":"Buz\u00e1s","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell\u2010 and Immunobiology Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura I.","family":"Yousif","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Medical Center Groningen University of Groningen Groningen The Netherlands"},{"name":"Division of Experimental Cardiology, Department of Cardiology, Thorax Center Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter C.","family":"Meijers","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Medical Center Groningen University of Groningen Groningen The Netherlands"},{"name":"Division of Experimental Cardiology, Department of Cardiology, Thorax Center Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"Radovits","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9la","family":"Merkely","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Ferdinandy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary"},{"name":"Pharmahungary 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