Immunosuppressive Therapy of Biopsy-Proven, Virus-Negative, Autoimmune/Immune-Mediated Myocarditis—Focus on Azathioprine: A Review of Existing Evidence and Future Perspectives

Grzechocińska, Justyna; Tymińska, Agata; Giordani, Andrea Silvio; Wysińska, Julia; Ostrowska, Ewa; Baritussio, Anna; Caforio, Alida L.P.; Grabowski, Marcin; Marcolongo, R; Ozierański, Krzysztof

doi:10.3390/biology12030356

Cited by 3 publications

(1 citation statement)

References 55 publications

(102 reference statements)

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“…Translationally, it is unknown whether CD4 + CTLs can contribute to cardiac damage in humans, but defining their antigen specificity may be challenging. Of note, immune suppressive therapies are generally used in myocarditis patients negative for viruses but positive for autoantibodies [68,69]. If antigenspecific T cells are identified as mediators of heart tissue destruction, the use of antigenspecific T cell therapies is not expected to interfere with the effects of immune suppressants.…”

Section: Discussionmentioning

confidence: 99%

Investigation into Cardiac Myhc-α 334–352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity

Sur,

Rasquinha,

Mone

et al. 2024

Cells

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Myocarditis is one of the major causes of heart failure in children and young adults and can lead to dilated cardiomyopathy. Lymphocytic myocarditis could result from autoreactive CD4+ and CD8+ T cells, but defining antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57BL/6J mice specific to cardiac myosin heavy chain (Myhc)-α 334–352 and found that Myhc-α-specific TCRs were expressed in both CD4+ and CD8+ T cells. To investigate if the phenotype is more pronounced in a myocarditis-susceptible genetic background, we backcrossed with A/J mice. At the fourth generation of backcrossing, we observed that Tg T cells from naïve mice responded to Myhc-α 334–352, as evaluated by proliferation assay and carboxyfluorescein succinimidyl ester staining. The T cell responses included significant production of mainly pro-inflammatory cytokines, namely interferon (IFN)-γ, interleukin-17, and granulocyte macrophage-colony stimulating factor. While the naïve Tg mice had isolated myocardial lesions, immunization with Myhc-α 334–352 led to mild myocarditis, suggesting that further backcrossing to increase the percentage of A/J genome close to 99.99% might show a more severe disease phenotype. Further investigations led us to note that CD4+ T cells displayed the phenotype of cytotoxic T cells (CTLs) akin to those of conventional CD8+ CTLs, as determined by the expression of CD107a, IFN-γ, granzyme B natural killer cell receptor (NKG)2A, NKG2D, cytotoxic and regulatory T cell molecules, and eomesodermin. Taken together, the transgenic system described in this report may be a helpful tool to distinguish the roles of cytotoxic cardiac antigen-specific CD4+ T cells vs. those of CD8+ T cells in the pathogenesis of myocarditis.

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Section: Discussionmentioning

confidence: 99%

Investigation into Cardiac Myhc-α 334–352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity

Sur,

Rasquinha,

Mone

et al. 2024

Cells

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Acute myocarditis: an overview of pathogenesis, diagnosis and management

ZAFEIRI,

KNOTT,

LAMPEJO

2024

Panminerva Med

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Giant cell myocarditis in modern clinical practice

Lasica,

Đukanović,

Zdravković

et al. 2023

Medicinska istraživanja

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Giant cell myocarditis is a rare but extremely severe disease with a frequent need for heart transplantation and a high mortality rate. To this day, the most common reason for the occurrence of this disease has not been precisely determined, but its frequent association with autoimmune diseases speaks in favor of autoimmune etiology. Clinically, it is presented to the greatest extent by symptoms and signs of acute heart failure and ventricular rhythm disturbances, which are registered in as many as half of the patients. Arrhythmias can be accompanied by the occurrence of palpitations, repeated syncope, and even sudden cardiac death. A severe degree of acute heart failure in hemodynamically unstable patents who respond inadequately to the administered therapy for heart failure and refractory heart rhythm disorders and/or conduction disorders that are common in these patients should always raise suspicion of giant cell myocarditis. Given that changes in electrocardiogram, echocardiography and positive biomarker values are not strictly specific for this disease, the diagnosis of giant cell myocarditis is most often established by endomyocardial biopsy, especially in patients with the fulminant form of the disease. Timely endomyocardial biopsy enables not only quick and accurate diagnosis, but also early administration of immunosuppressive therapy, which greatly improves the outcome in these patients. Pathohistological verification of this disease is important so as to rule out cardiac sarcoidosis and other granulomatous infectious and non-infectious diseases. Given that in a large number of patients the disease has a fulminant course, early and rapid diagnosis, application of inotropic stimulation and mechanical circulatory support in hemodynamically unstable patients and adequate modern therapeutic regimen can largely reduce mortality in these patients, which is still high despite modern diagnostics and therapeutic progress of medicine.

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Immunosuppressive Therapy of Biopsy-Proven, Virus-Negative, Autoimmune/Immune-Mediated Myocarditis—Focus on Azathioprine: A Review of Existing Evidence and Future Perspectives

Cited by 3 publications

References 55 publications

Investigation into Cardiac Myhc-α 334–352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity

Investigation into Cardiac Myhc-α 334–352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity

Acute myocarditis: an overview of pathogenesis, diagnosis and management

Giant cell myocarditis in modern clinical practice

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