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Preclinical mouse models of immune checkpoint inhibitor-associated myocarditis

Nature Cardiovascular Research volume 4, pages 526–538 (2025)Cite this article

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Abstract

In this Review, we present a comprehensive analysis of preclinical models used to study immune checkpoint inhibitor-associated myocarditis (hereafter ICI-myocarditis), a potentially lethal immune-related adverse event. We begin by providing an overview of immune checkpoint inhibitors, highlighting how their efficacy in cancer treatment is counterbalanced by their predisposition to cause immune-related adverse events. Next, we draw from human data to identify disease features that an effective mouse model should ideally mimic. After that, we present a critical evaluation of a wide variety of existing mouse models including genetic, pharmacological and humanized models. We summarize insights gathered about the underlying mechanisms of ICI-myocarditis and the role of mouse models in these discoveries. We conclude with a perspective on the future of preclinical models, highlighting potential model improvements and research directions that could strengthen our understanding of ICI-myocarditis, ultimately improving patient outcomes.

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Fig. 1: Immunopathogenesis of ICI-myocarditis.
Fig. 2: Heart-intrinsic factors modify disease severity.

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References

  1. Haslam, A. & Prasad, V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw. Open 2, e192535 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tan, S., Day, D., Nicholls, S. J. & Segelov, E. Immune checkpoint inhibitor therapy in oncology. JACC CardioOncol. 4, 579–597 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pauken, K. E., Dougan, M., Rose, N. R., Lichtman, A. H. & Sharpe, A. H. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol. 40, 511–523 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ramos-Casals, M. et al. Immune-related adverse events of checkpoint inhibitors. Nat. Rev. Dis. Primers 6, 38 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Postow Michael, A., Sidlow, R. & Hellmann Matthew, D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721–1728 (2018). Meta-analysis describing incidence and mortality rates of various irAEs, including ICI-myocarditis.

  7. Johnson Douglas, B. et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749–1755 (2016). Fundamental work describing two patients with fulminant ICI-myocarditis, with molecular characterization of the pathophysiology.

  8. Mahmood, S. S. et al. Myocarditis in patients treated with immune checkpoint inhibitors. J. Am. Coll. Cardiol. 71, 1755–1764 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Al-Kindi, S. G. & Oliveira, G. H. Reporting of immune checkpoint inhibitor-associated myocarditis. Lancet 392, 382–383 (2018).

    Article  PubMed  Google Scholar 

  10. Moslehi, J. J., Salem, J.-E., Sosman, J. A., Lebrun-Vignes, B. & Johnson, D. B. Rapid increase in reporting of fatal immune checkpoint inhibitor associated myocarditis. Lancet 391, 933 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Salem, J.-E. et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 19, 1579–1589 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mestas, J. & Hughes, C. C. W. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Hu, J.-R. et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc. Res. 115, 854–868 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tan, M. H. et al. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin. Diabetes Endocrinol. 5, 1 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zamami, Y. et al. Factors associated with immune checkpoint inhibitor-related myocarditis. JAMA Oncol. 5, 1635–1637 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fenioux, C. et al. Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis. Nat. Med. 29, 3100–3110 (2023). Describes increased rates of ICI-myocarditis, myositis and myasthenia gravis in patients with thymic epithelial tumors treated with ICI.

  17. Chen, Q. et al. Fatal myocarditis and rhabdomyolysis induced by nivolumab during the treatment of type B3 thymoma. Clin. Toxicol. 56, 667–671 (2018).

    Article  CAS  Google Scholar 

  18. Hyun, J.-W. et al. Fatal simultaneous multi-organ failure following pembrolizumab treatment for refractory thymoma. Clin. Lung Cancer 21, e74–e77 (2020).

    Article  PubMed  Google Scholar 

  19. Nguyen, L. S. et al. Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept. J. Immunother. Cancer 10, e004699 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yousif, L. I. et al. Risk factors for immune checkpoint inhibitor-mediated cardiovascular toxicities. Curr. Oncol. Rep. 25, 753–763 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lyon, A. R., Yousaf, N., Battisti, N. M. L., Moslehi, J. & Larkin, J. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 19, e447–e458 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Kalinoski, H. et al. Injury-induced myosin-specific tissue-resident memory T cells drive immune checkpoint inhibitor myocarditis. Proc. Natl Acad. Sci. USA 121, e2323052121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pathak, R. et al. Immune checkpoint inhibitor-induced myocarditis with myositis/myasthenia gravis overlap syndrome: a systematic review of cases. Oncologist 26, 1052–1061 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Aldrich, J. et al. Inflammatory myositis in cancer patients receiving immune checkpoint inhibitors. Arthritis Rheumatol. 73, 866–874 (2021).

    Article  CAS  PubMed  Google Scholar 

  25. Power, J. R. et al. Electrocardiographic manifestations of immune checkpoint inhibitor myocarditis. Circulation 144, 1521–1523 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lehmann, L. H. et al. Cardiomuscular biomarkers in the diagnosis and prognostication of immune checkpoint inhibitor myocarditis. Circulation 148, 473–486 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pradhan, R., Nautiyal, A. & Singh, S. Diagnosis of immune checkpoint inhibitor-associated myocarditis: a systematic review. Int. J. Cardiol. 296, 113–121 (2019).

    Article  PubMed  Google Scholar 

  28. Champion, S. N. & Stone, J. R. Immune checkpoint inhibitor associated myocarditis occurs in both high-grade and low-grade forms. Mod. Pathol. 33, 99–108 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Palaskas, N. L. et al. Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy. Eur. J. Heart Fail. 23, 1725–1735 (2021). Outlines the histopathological features of ICI-myocarditis across a wide range of samples with different disease severity.

  30. Sobol, I., Chen, C. L., Mahmood, S. S. & Borczuk, A. C. Histopathologic characterization of myocarditis associated with immune checkpoint inhibitor therapy. Arch. Pathol. Lab. Med. 144, 1392–1396 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ma, P. et al. Expansion of pathogenic cardiac macrophages in immune checkpoint inhibitor myocarditis. Circulation 149, 48–66 (2024). Investigates the role of macrophages in ICI-myocarditis.

  32. Rizzo, S., De Gaspari, M. & Basso, C. Immune checkpoint inhibitor myocarditis: a call for standardized histopathologic criteria. Eur. J. Heart Fail. 23, 1736–1738 (2021).

    Article  PubMed  Google Scholar 

  33. Norwood, T. G. et al. Smoldering myocarditis following immune checkpoint blockade. J. Immunother. Cancer 5, 91 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lehmann, L. H. et al. Clinical strategy for the diagnosis and treatment of immune checkpoint inhibitor-associated myocarditis: a narrative review. JAMA Cardiol. 6, 1329–1337 (2021).

    Article  PubMed  Google Scholar 

  35. Bonaca, M. P. et al. Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology. Circulation 140, 80–91 (2019). Provides a standardized criteria for diagnosing ICI-myocarditis based on diagnostic certainty and further classifying based on disease severity.

  36. Moslehi, J. & Salem, J.-E. Immune checkpoint inhibitor myocarditis treatment strategies and future directions. JACC CardioOncol. 4, 704–707 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Palaskas, N., Lopez‐Mattei, J., Durand, J. B., Iliescu, C. & Deswal, A. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J. Am. Heart Assoc. 9, e013757 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Frascaro, F. et al. Immune checkpoint inhibitors-associated myocarditis: diagnosis, treatment and current status on rechallenge. J. Clin. Med. 12, 7737 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thuny, F. et al. Management of immune checkpoint inhibitor-induced myocarditis: the French Working Group’s plea for a pragmatic approach. JACC CardioOncol. 3, 157 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wei, S. C. et al. A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention. Cancer Discov. 11, 614–625 (2021). Developed a mouse model of myocarditis through combined deficiency of PD-1 and CTLA4 in C57BL/6 mice.

  41. Salem, J.-E. et al. Abatacept/ruxolitinib and screening for concomitant respiratory muscle failure to mitigate fatality of immune-checkpoint inhibitor myocarditis. Cancer Discov. 13, 1100–1115 (2023). Describes the use of abatacept and ruxolitinib to prevent mortality in ICI-myocarditis.

  42. Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995). Studies the effect of CTLA4 deficiency in mouse models.

  43. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270, 985–988 (1995). Also studies the effect of CTLA4 deficiency in mouse models.

    Article  CAS  PubMed  Google Scholar 

  44. Oosterwegel, M. A. et al. The role of CTLA-4 in regulating TH2 differentiation. J. Immunol. 163, 2634–2639 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Lühder, F., Chambers, C., Allison, J. P., Benoist, C. & Mathis, D. Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells. Proc. Natl. Acad. Sci. USA 97, 12204–12209 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Klocke, K., Sakaguchi, S., Holmdahl, R. & Wing, K. Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Proc. Natl Acad. Sci. USA 113, E2383–E2392 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001). Investigates cardiovascular effects of PD-1 deficiency in mice.

  49. Okazaki, T. et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat. Med. 9, 1477–1483 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, J. et al. Establishment of NOD-Pdcd1−/− mice as an efficient animal model of type I diabetes. Proc. Natl. Acad. Sci. USA 102, 11823–11828 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Richard, M. L. & Gilkeson, G. Mouse models of lupus: what they tell us and what they don’t. Lupus Sci. Med. 5, e000199 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lucas, J. A. et al. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J. Immunol. 181, 2513–2521 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Wang, J. et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int. Immunol. 22, 443–452 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Zhang, Y. et al. Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis. Sci. Transl. Med. 14, eabo1981 (2022). Investigates potential drivers of sex differences in the severity of ICI-myocarditis.

  55. Axelrod, M. L. et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature 611, 818–826 (2022). Identifies MHC-I-restricted antigenic regions of α-myosin in both human samples and mouse models of ICI-myocarditis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Okazaki, T. & Honjo, T. The PD-1–PD-L pathway in immunological tolerance. Trends Immunol. 27, 195–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Okazaki, T. et al. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J. Exp. Med. 208, 395–407 (2011). Describes the effects of combination PD-1 and LAG3 deficiency in mice.

  58. Miyazaki, T., Dierich, A., Benoist, C. & Mathis, D. Independent modes of natural killing distinguished in mice lacking Lag3. Science 272, 405–408 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Woo, S.-R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Michel, L. et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur. Heart J. 43, 316–329 (2022).

    Article  CAS  PubMed  Google Scholar 

  61. Xia, W., Zou, C., Chen, H., Xie, C. & Hou, M. Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling. Cell Death Dis. 11, 575 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gergely, T. G. et al. Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment. Br. J. Pharmacol. 180, 740–761 (2023).

    Article  CAS  PubMed  Google Scholar 

  63. Sun, S.-J. et al. Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS–STING activation. Nat. Commun. 15, 6640 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Won, T. et al. Cardiac myosin-specific autoimmune T cells contribute to immune-checkpoint-inhibitor-associated myocarditis. Cell Rep. 41, 111611 (2022). Developed a mouse model of ICI-myocarditis and characterized immunopathogenesis in A/J mice treated with anti-PD-1 antibodies.

  65. Massilamany, C., Gangaplara, A., Chapman, N., Rose, N. & Reddy, J. Detection of cardiac myosin heavy chain-α-specific CD4 cells by using MHC class II/IAk tetramers in A/J mice. J. Immunol. Methods 372, 107–118 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Tam, W. Y. & Cheung, K.-K. Phenotypic characteristics of commonly used inbred mouse strains. J. Mol. Med. 98, 1215–1234 (2020).

    Article  PubMed  Google Scholar 

  67. Roche, J. A. et al. Myofiber damage precedes macrophage infiltration after in vivo injury in dysferlin-deficient A/J mouse skeletal muscle. Am. J. Pathol. 185, 1686–1698 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dillingham, B. C. et al. Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice. J. Neurol. Sci. 356, 157–162 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sellers, R. S., Clifford, C. B., Treuting, P. M. & Brayton, C. Immunological variation between inbred laboratory mouse strains: points to consider in phenotyping genetically immunomodified mice. Vet. Pathol. 49, 32–43 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Lee, B. H., Gauna, A. E., Pauley, K. M., Park, Y.-J. & Cha, S. Animal models in autoimmune diseases: lessons learned from mouse models for Sjögren’s syndrome. Clin. Rev. Allergy Immunol. 42, 35–44 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hu, Y., Nakagawa, Y., Purushotham, K. R. & Humphreys-Beher, M. G. Functional changes in salivary glands of autoimmune disease-prone NOD mice. Am. J. Physiol. 263, E607–E614 (1992).

    CAS  PubMed  Google Scholar 

  72. Humphreys-Beher, M. G. Animal models for autoimmune disease-associated xerostomia and xerophthalmia. Adv. Dent. Res. 10, 73–75 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Fontes, J. A. et al. Complete Freund’s adjuvant induces experimental autoimmune myocarditis by enhancing IL-6 production during initiation of the immune response. Immun. Inflamm. Dis. 5, 163–176 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Čiháková, D., Sharma, R. B., Fairweather, D., Afanasyeva, M. & Rose, N. R. Animal models for autoimmune myocarditis and autoimmune thyroiditis. In Autoimmunity: Methods and Protocols (ed. Perl, A.) 175–193 (Humana Press, 2004).

  75. Neu, N. et al. Cardiac myosin induces myocarditis in genetically predisposed mice. J. Immunol. 139, 3630–3636 (1987).

    Article  CAS  PubMed  Google Scholar 

  76. Pummerer, C. L. et al. Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice. J. Clin. Invest. 97, 2057–2062 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Valaperti, A. et al. CD11b+ monocytes abrogate TH17 CD4+ T cell-mediated experimental autoimmune myocarditis. J. Immunol. 180, 2686–2695 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Baldeviano, G. C. et al. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circ. Res. 106, 1646–1655 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Afanasyeva, M., Georgakopoulos, D. & Rose, N. R. Autoimmune myocarditis: cellular mediators of cardiac dysfunction. Autoimmun. Rev. 3, 476–486 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Afanasyeva, M. et al. Quantitative analysis of myocardial inflammation by flow cytometry in murine autoimmune myocarditis: correlation with cardiac function. Am. J. Pathol. 164, 807–815 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Rose, N. R., Wolfgram, L. J., Herskowitz, A. & Beisel, K. W. Postinfectious autoimmunity: two distinct phases of Coxsackievirus B3-induced myocarditis. Ann. N. Y. Acad. Sci. 475, 146–156 (1986).

    Article  CAS  PubMed  Google Scholar 

  82. Fairweather, D., Kaya, Z., Shellam, G. R., Lawson, C. M. & Rose, N. R. From infection to autoimmunity. J. Autoimmun. 16, 175–186 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Fairweather, D. & Rose, N. R. Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity. Methods 41, 118–122 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. do Canto Cavalheiro, M. M. & Leon, L. L. In Handbook of Animal Models of Infection (eds Zak, O. & Sande, M. A.) 801–810 (Academic, 1999).

  85. Grabie, N. et al. IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis. J. Clin. Invest. 111, 671–680 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tarrio, M. L., Grabie, N., Bu, D., Sharpe, A. H. & Lichtman, A. H. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J. Immunol. 188, 4876–4884 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Van der Borght, K. et al. Myocarditis elicits dendritic cell and monocyte infiltration in the heart and self-antigen presentation by conventional type 2 dendritic cells. Front. Immunol. 9, 2714 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Eriksson, U. et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat. Med. 9, 1484–1490 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Machino‐Ohtsuka, T. et al. Tenascin‐C aggravates autoimmune myocarditis via dendritic cell activation and TH17 cell differentiation. J. Am. Heart Assoc. 3, e001052 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Blyszczuk, P. et al. Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circ. Res. 105, 912–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Tsuruoka, K. et al. Exacerbation of autoimmune myocarditis by an immune checkpoint inhibitor is dependent on its time of administration in mice. Int. J. Cardiol. 313, 67–75 (2020).

    Article  PubMed  Google Scholar 

  92. Seko, Y., Yagita, H., Okumura, K., Azuma, M. & Nagai, R. Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3. Cardiovasc. Res. 75, 158–167 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Machado, F. S. et al. Current understanding of immunity to Trypanosoma cruzi infection and pathogenesis of Chagas disease. Semin. Immunopathol. 34, 753–770 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gutierrez, F. R. S. et al. Regulation of Trypanosoma cruzi-induced myocarditis by programmed death cell receptor 1. Infect. Immun. 79, 1873–1881 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Engman, D. M., Dragon, E. A. & Donelson, J. E. Human humoral immunity to hsp70 during Trypanosoma cruzi infection. J. Immunol. 144, 3987–3991 (1990).

    Article  CAS  PubMed  Google Scholar 

  96. Levin, M. J. et al. Identification of major Trypanosoma cruzi antigenic determinants in chronic Chagas’ heart disease. Am. J. Trop. Med. Hyg. 41, 530–538 (1989).

    Article  CAS  PubMed  Google Scholar 

  97. Van Voorhis, W. C. & Eisen, H. Fl-160. A surface antigen of Trypanosoma cruzi that mimics mammalian nervous tissue. J. Exp. Med. 169, 641–652 (1989).

    Article  PubMed  Google Scholar 

  98. Taqueti, V. R. et al. T-bet controls pathogenicity of CTLs in the heart by separable effects on migration and effector activity. J. Immunol. 177, 5890–5901 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Grabie, N. et al. Neutrophils sustain pathogenic CD8+ T cell responses in the heart. Am. J. Pathol. 163, 2413–2420 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Grabie, N. et al. Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell-mediated injury in the heart. Circulation 116, 2062–2071 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Marty, R. R. et al. MyD88 signaling controls autoimmune myocarditis induction. Circulation 113, 258–265 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Horiguchi, H. et al. ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis. Commun. Biol. 6, 965 (2023). Outlines a role for inflammatory fibroblasts in the pathogenesis of ICI-myocarditis.

  103. Du, S. et al. PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes. J. Thorac. Oncol. 13, 510–520 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Hayashi, T., Lim, K. R. Q., Kovacs, A. & Mann, D. L. Recurrent adrenergic stress provokes persistent myocarditis in PD-1-deficient mice. JACC Basic Transl. Sci. 8, 1503–1517 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rubio‐Infante, N. et al. Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice. ESC Heart Fail. 11, 1249–1257 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Varga, Z. et al. Prior cardiac ischemic injury exacerbates immune checkpoint inhibitor-induced cardiotoxicity. Cardiovasc. Res. 120, cvae088.091 (2024).

    Article  Google Scholar 

  107. Dendrou, C. A., Petersen, J., Rossjohn, J. & Fugger, L. HLA variation and disease. Nat. Rev. Immunol. 18, 325–339 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. Hahn, M., Nicholson, M. J., Pyrdol, J. & Wucherpfennig, K. W. Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor. Nat. Immunol. 6, 490–496 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lang, H. L. E. et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol. 3, 940–943 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Sethi, D. K. et al. A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC. J. Exp. Med. 208, 91–102 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yang, J. et al. Autoreactive T cells specific for insulin B:11–23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes. Proc. Natl Acad. Sci. USA 111, 14840–14845 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jensen, P. E. & Zhou, Z. Structural characteristics of HLA-DQ that may impact DM editing and susceptibility to type-1 diabetes. Front. Immunol. 4, 262 (2013).

    PubMed  PubMed Central  Google Scholar 

  113. McKenna, C. J., Codd, M. B., McCann, H. A. & Sugrue, D. D. Idiopathic dilated cardiomyopathy: familial prevalence and HLA distribution. Heart 77, 549–552 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Limas, C. J. Autoimmunity in dilated cardiomyopathy and the major histocompatibility complex. Int. J. Cardiol. 54, 113–116 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Liu, J., Purdy, L. E., Rabinovitch, S., Jevnikar, A. M. & Elliott, J. F. Major DQ8-restricted T-cell epitopes for human GAD65 mapped using human CD4, DQA1*0301, DQB1*0302 transgenic IA(null) NOD mice. Diabetes 48, 469–477 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Elliott, J. F. et al. Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice. Proc. Natl Acad. Sci. USA 100, 13447–13452 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Taneja, V. et al. Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice. J. Mol. Cell. Cardiol. 42, 1054–1064 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Taylor, J. A. et al. A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ81. J. Immunol. 172, 2651–2658 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Racine, J. J. et al. HLA-DQ8 supports development of insulitis mediated by insulin-reactive human TCR-transgenic T cells in nonobese diabetic mice. J. Immunol. 211, 1792–1805 (2023).

    Article  PubMed  Google Scholar 

  120. Racine, J. J. et al. Murine MHC-deficient nonobese diabetic mice carrying human HLA-DQ8 develop severe myocarditis and myositis in response to anti-PD-1 immune checkpoint inhibitor cancer therapy. J. Immunol. 212, 1287–1306 (2024).

    Article  CAS  PubMed  Google Scholar 

  121. Hayward, S. L. et al. CD4 T cells play major effector role and CD8 T cells initiating role in spontaneous autoimmune myocarditis of HLA-DQ8 transgenic IAb knockout nonobese diabetic mice. J. Immunol. 176, 7715–7725 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Čiháková, D. T cells and macrophages drive pathogenesis of immune checkpoint inhibitor myocarditis. Circulation 149, 67–69 (2024).

    Article  PubMed  Google Scholar 

  123. Lv, H. et al. Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest. 121, 1561–1573 (2011). Shows how lack of expression of α-myosin in the thymus leads to a breach of central tolerance, which drives myocarditis. Enforced expression of α-myosin in the thymus mitigated the development of myocarditis.

  124. Weiss, A. & Leinwand, L. A. The mammalian myosin heavy chain gene family. Annu. Rev. Cell Dev. Biol. 12, 417–439 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Lompré, A. M., Nadal-Ginard, B. & Mahdavi, V. Expression of the cardiac ventricular α- and β-myosin heavy chain genes is developmentally and hormonally regulated. J. Biol. Chem. 259, 6437–6446 (1984).

    Article  PubMed  Google Scholar 

  126. Lompre, A. M. et al. Species- and age-dependent changes in the relative amounts of cardiac myosin isoenzymes in mammals. Dev. Biol. 84, 286–290 (1981).

    Article  CAS  PubMed  Google Scholar 

  127. Clark, W. A., Chizzonite, R. A., Everett, A. W., Rabinowitz, M. & Zak, R. Species correlations between cardiac isomyosins. A comparison of electrophoretic and immunological properties. J. Biol. Chem. 257, 5449–5454 (1982).

    Article  CAS  PubMed  Google Scholar 

  128. Miyata, S., Minobe, W., Bristow, M. R. & Leinwand, L. A. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ. Res. 86, 386–390 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Blum, S. M. et al. Immune responses in checkpoint myocarditis across heart, blood and tumour. Nature 636, 215–223 (2024).

    Article  CAS  PubMed  Google Scholar 

  130. Li, Y., Heuser, J. S., Cunningham, L. C., Kosanke, S. D. & Cunningham, M. W. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J. Immunol. 177, 8234–8240 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Stavrakis, S. et al. Activating autoantibodies to the β-1 adrenergic and M2 muscarinic receptors facilitate atrial fibrillation in patients with Graves’ hyperthyroidism. J. Am. Coll. Cardiol. 54, 1309–1316 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mascaro-Blanco, A. et al. Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies. Autoimmunity 41, 442–453 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kohlgruber, A. C. et al. High-throughput discovery of MHC class I- and II-restricted T cell epitopes using synthetic cellular circuits. Nat. Biotechnol. 43, 623–634 (2024).

  134. Ashby, K. M. & Hogquist, K. A. A guide to thymic selection of T cells. Nat. Rev. Immunol. 24, 103–117 (2024).

    Article  CAS  PubMed  Google Scholar 

  135. Racine, J. J. et al. Improved murine MHC-deficient HLA transgenic NOD mouse models for type 1 diabetes therapy development. Diabetes 67, 923–935 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Murphy, E. Estrogen signaling and cardiovascular disease. Circ. Res. 109, 687–696 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Gourdie, R. G., Dimmeler, S. & Kohl, P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat. Rev. Drug Discov. 15, 620–638 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Cai, K. et al. Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches. Pharmacol. Res. 206, 107281 (2024).

    Article  CAS  PubMed  Google Scholar 

  139. Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Berry, C. J. et al. Effects of deep sedation or general anesthesia on cardiac function in mice undergoing cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 11, 16 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the following funding sources that made this work possible: AHA predoctoral fellowship award ID 25PRE1375723 (https://doi.org/10.58275/AHA.25PRE1375723.pc.gr.227181), Vanderbilt Medical Scientist Training Program T32 training grant, the NIGMS of the National Institutes of Health (award number T32GM007347), NIH 5R01HL156021-04 (Immunologic and antigenic drivers of immune checkpoint inhibitor-associated myocarditis), NIH 5R01CA227481-05 (Patient- and tumor-specific biomarkers and mechanisms that predict irAEs resulting from checkpoint inhibition), 5P30CA068485-29 (Breast Cancer Research Program), NIH 5R01HL155990-04 (Long-term cardiovascular sequelae of cancer immunotherapies), NIH 5R01HL141466-05 (Novel mechanisms and predictors of VEGF receptor inhibitor-associated hypertension), 5P30CA068485-29 (Translational research and interventional oncology research Program), NIH P01 HL141084 and NIH R01 HL160688.

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Authors and Affiliations

  1. Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, TN, USA

    Reilly G. Fankhauser

  2. Department of Medicine, Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    Douglas B. Johnson & Justin M. Balko

  3. Section of Cardio-Oncology and Immunology, Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, CA, USA

    Javid J. Moslehi

  4. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Justin M. Balko

  5. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Justin M. Balko

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  1. Reilly G. Fankhauser
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Contributions

R.G.F. performed conceptualization, writing (original draft), visualization, review and editing. J.M.B., J.J.M. and D.B.J. performed content oversight, guidance, review and editing.

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Correspondence to Justin M. Balko.

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Competing interests

R.G.F. has no conflicts of interest to disclose. J.J.M. has consulting or advisory roles for Pfizer, Novartis, Bristol Myers Squibb, Deciphera, Takeda, AstraZeneca, Regeneron, Myovant, Silverback Therapeutics, Kurome Therapeutics, Kiniksa Pharmaceuticals, Daiichi Sankyo, BeiGene, IQVIA, AskBio, Labcorp, Paladin, Bitterroot Bio, Repare Therapeutics and Cytokinetics. J.J.M. is a co-inventor of a patent related to the use of abatacept in the treatment of ICI-myocarditis. D.B.J. has served on advisory boards or as a consultant for AstraZeneca, BMS, Jackson Laboratory, Merck, Novartis, Pfizer, Targovax and Teiko and has received research funding from BMS and Incyte. J.M.B. reports grants from the NIH/NCI, the DOD, Susan G. Komen and the BCRF during the conduct of the study. J.M.B. also reports grants from Genentech and Incyte and personal fees from AstraZeneca and Eli Lilly outside the submitted work; in addition, J.M.B. has a patent for MHC-I and MHC-II expression to predict immunotherapy outcomes issued.

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Nature Cardiovascular Research thanks Marinos Kallikourdis, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Fankhauser, R.G., Johnson, D.B., Moslehi, J.J. et al. Preclinical mouse models of immune checkpoint inhibitor-associated myocarditis. Nat Cardiovasc Res 4, 526–538 (2025). https://doi.org/10.1038/s44161-025-00640-2

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