PhD Scientific Days 2025

Poster Session I. - F: Pharmaceutical Sciences and Health Technologies

Immune Dysregulation in Clozapine-Induced Myocarditis

Name of the presenter

Jakab Márk

Institute/workplace of the presenter

Semmelweis University, Departement of Pharmacology and Pharmacotherapy

Authors

Márk E. Jakab^1,2,3,4, Zsombor I. Hegedűs^1,2,3,4, Lilla Szabó^1,2,3,4, Tamás Kovács^1,2,3,4, Andrea Kovács^1,2,3,4, Zoltán V. Varga^1,2,3,4

1: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
2: Center for Pharmacology and Drug Research & Development, Budapest, Hungary
3: HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
4: MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary

Text of the abstract

Introduction: Pharmacovigilance data identify clozapine, a highly effective antipsychotic for treatment-resistant schizophrenia, as the leading cause of drug-induced myocarditis. No specific treatment exists; discontinuation remains the primary approach, risking psychiatric decompensation. The mechanisms underlying clozapine-induced myocarditis (CIM) remain unclear. Evidence points to eosinophilic infiltration and a Th2-driven immune response, but other factors—including innate lymphoid cells (ILCs) and pro-inflammatory cytokines—may contribute.
Aims: We aimed to characterize the immune alterations in a murine model of CIM, focusing on cytokine expression and immune cell infiltration.
Methods: Male BALB/c mice (8 weeks old) received intraperitoneal injections of clozapine (25 mg/kg or 35 mg/kg) or vehicle control for 21 days. After treatment, cardiac tissue underwent histopathological and transcriptomic analysis to assess inflammatory markers, cytokine gene expression, and leukocyte infiltration.
Results: Clozapine administration induced dose-dependent myocardial inflammation marked by leukocyte infiltration and focal necrosis. Transcriptomic profiling showed increased IL-13, IL-33, and eosinophil-attracting chemokines CCL11 and CCL24 (eotaxins). Elevated IL-17A was also observed, while IFN-γ, TNF-α, and IL-1β remained unchanged.
Conclusion: Our findings indicate that clozapine-induced myocarditis involves immune dysregulation marked by Th2- and Th17-related cytokine signatures without classical pro-inflammatory cytokine upregulation. The concurrent increase in IL-13, IL-33, and eotaxins suggests an eosinophilic and type 2 inflammatory milieu, potentially driven by adaptive and innate lymphoid pathways. This immune profile offers novel mechanistic insights into CIM and a basis for exploring immunomodulatory interventions targeting specific cytokines and cell populations.
Funding: Momentum Research Grant from the Hungarian Academy of Sciences (LP- 2021-38 to ZVV).