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To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI\/II\u2212\/\u2212.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR\/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell\u2013mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti\u2013PD-1 ICI-induced treatment. Additionally, anti\u2013PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.<\/jats:p>","DOI":"10.4049\/jimmunol.2300841","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T15:05:55Z","timestamp":1709305555000},"page":"1287-1306","source":"Crossref","is-referenced-by-count":18,"title":["Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti\u2013PD-1 Immune Checkpoint Inhibitor Cancer Therapy"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5514-3074","authenticated-orcid":false,"given":"Jeremy J","family":"Racine","sequence":"first","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F","family":"Bachman","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Gang","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-8122","authenticated-orcid":false,"given":"Adel","family":"Misherghi","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"},{"name":"College of the Atlantic , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3987-2899","authenticated-orcid":false,"given":"Raheem","family":"Khadour","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"},{"name":"College of the Atlantic , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7571-2429","authenticated-orcid":false,"given":"Sana","family":"Kaisar","sequence":"additional","affiliation":[{"name":"Imperial College London , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7888-1895","authenticated-orcid":false,"given":"Olivia","family":"Bedard","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Imperial College London , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0954-381X","authenticated-orcid":false,"given":"Annie","family":"Abbott","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5555-9122","authenticated-orcid":false,"given":"Elvira","family":"Forte","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Rainer","sequence":"additional","affiliation":[{"name":"Medical University of Graz , Graz ,","place":["Austria"]},{"name":"BioTechMed Graz , Graz ,","place":["Austria"]},{"name":"BKH St. Johann in Tirol , St. Johann in Tirol ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"},{"name":"Imperial College London , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9932-4109","authenticated-orcid":false,"given":"Susanne","family":"Sattler","sequence":"additional","affiliation":[{"name":"Imperial College London , London ,","place":["United Kingdom"]},{"name":"Medical University of Graz , Graz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-5925","authenticated-orcid":false,"given":"David V","family":"Serreze","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"key":"2025020405483687700_r1","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/S1470-2045(18)30608-9","article-title":"Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study","volume":"19","author":"Salem","year":"2018","journal-title":"Lancet. 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