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

The Journal of Immunology, Год журнала: 2024, Номер 212(8), С. 1287 - 1306

Опубликована: Март 1, 2024

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving therapy, understanding fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops lower mortality than observed in previous HLA-DQ8 NOD 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-mediated absence classically selected CD8+ cells. These mice are highly susceptible acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, RNA sequencing analyses, we performed thorough characterization cardiac cells, identifying shared unique characteristics both populations. Taken together, this report details features rare, but lethal clinical presentation overlapping myositis therapy. This study sheds light on mechanisms provides basis further detailed analyses diagnostic therapeutic strategies.

Язык: Английский

---

The PD-1–PD-L1 pathway maintains an immunosuppressive environment essential for neonatal heart regeneration

Nature Cardiovascular Research, Год журнала: 2024, Номер 3(3), С. 389 - 402

Опубликована: Март 1, 2024

Язык: Английский

---

Preclinical models of cardiotoxicity from immune checkpoint inhibitor therapy

Basic Research in Cardiology, Год журнала: 2024, Номер unknown

Опубликована: Июль 22, 2024

Abstract Immune checkpoint inhibitor (ICI) therapy represents a ground-breaking paradigm in cancer treatment, harnessing the immune system to combat malignancies by targeting checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). The use of ICI generates distinctive immune-related adverse events (irAEs) including cardiovascular toxicity, necessitating targeted research efforts. This comprehensive review explores preclinical models dedicated ICI-mediated complications myocarditis. Tailored myocardial toxicities highlight key role CD8 + T cells, emphasizing profound impact on maintaining cardiac integrity. Cytokines macrophages were identified possible driving factors disease progression, at same time, initial data antigens responsible are emerging. implications contributing thoracic radiation, autoimmune disorder, presence itself increasingly understood. Besides myocarditis, mouse unveiled an accelerated progression atherosclerosis, adding another layer for thorough understanding diverse processes involving signalling. aims discuss current cardiotoxicity their potential improving enhanced risk assessment diagnostics, offering targets innovative cardioprotective strategies. Lessons from can drive novel approaches research, extending insights areas infarction heart failure.

Язык: Английский

---

Mediators and mechanisms of immune checkpoint inhibitor‐associated myocarditis: Insights from mouse and human

Immunological Reviews, Год журнала: 2023, Номер 318(1), С. 70 - 80

Опубликована: Июль 14, 2023

The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell targeting cells but can frequently trigger autoimmune manifestations, termed immune-related adverse events (irAEs), affecting essentially any organ system. Among cardiovascular irAEs, myocarditis (irMyocarditis) is the most described and carries highest morbidity. currently recommended treatment for irMyocarditis potent immunosuppression with corticosteroids other agents, this limited evidence basis. cellular pathophysiology remains poorly understood, though mouse models human data have both implicated effector CD8

Язык: Английский

---

Immune-Checkpoint Inhibitor-Related Myocarditis: Where We Are and Where We Will Go

Angiology, Год журнала: 2023, Номер 75(10), С. 909 - 920

Опубликована: Сен. 12, 2023

Immune checkpoint inhibitors (ICIs) are specific monoclonal antibodies directed against inhibitory targets of the immune system, mainly represented by programmed death-1 (PD1) ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), thus enabling an amplified T-cell-mediated response cancer cells. These drugs have significantly improved prognosis in patients with advanced metastatic (e.g., melanoma, non-small cell lung cancer, renal carcinoma). However, uncontrolled activation anti-tumor T-cells could trigger excessive response, possibly responsible for multi-organ damage, including, among others, lymphocytic myocarditis. The incidence ICIs-induced myocarditis is underestimated affected poorly characterized. diagnosis management this condition based on expert opinion case reports. EKG ultrasound tests that can help identify at risk during treatment red flags, such as QRS complex enlargement narrowing global longitudinal strain (GLS). Therapy ICI-related immunosuppressors, fusion proteins. A future strategy involve use microRNAs. This review considers current state art immune-related adverse cardiovascular events, focusing histological clinical features, management, including treatments pharmacological targets.

Язык: Английский

---