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Isolation and Identification of Extravascular Immune Cells of the Heart
Published on: August 23, 2018
Engineered immunosuppressive dendritic cells protect against cardiac remodelling
Xiaoying Li1,2,3,4, Jiamin Li1,5, Guohua Li1,2,3
1Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Insights
Engineered immunosuppressive dendritic cells (iCDCs) effectively treat cardiac fibrosis and heart failure. This novel therapy improves cardiac function and perfusion in preclinical models without systemic toxicity.
Area of Science:
- Cardiovascular Research
- Immunology
- Regenerative Medicine
Background:
- Heart failure is a leading cause of death, with pathological cardiac fibrosis and declining function remaining untreatable.
- Chronic inflammation drives cardiac fibrosis after injury, but effective local immune modulation strategies are lacking.
- Dendritic cells (DCs) regulate immune responses and offer potential for therapeutic immune reprogramming in cardiac disease.
Purpose of the Study:
- To investigate the efficacy of engineered immunosuppressive and fibrosis-targeted dendritic cells (iCDCs) in preventing and reversing cardiac fibrosis and dysfunction.
- To elucidate the mechanisms underlying iCDC-mediated cardioprotection.
- To assess the safety and efficacy of iCDC therapy in preclinical models of cardiac disease.
Main Methods:
- Development of engineered immunosuppressive and fibrosis-targeted dendritic cells (iCDCs).
- Administration of iCDCs in mouse models of ischaemia-reperfusion injury, myocardial infarction, and pressure overload.
- Evaluation of cardiac fibrosis, perfusion, contractility, and immune cell activation.
- Assessment of iCDC therapy in a non-human primate model of myocardial infarction.
Main Results:
- iCDC therapy significantly reduced cardiac fibrosis, improved cardiac perfusion, and preserved contractility in multiple mouse models.
- Mechanistic studies revealed iCDCs suppress immune and stromal cell activation and promote regulatory T cell expansion.
- iCDC treatment in non-human primates demonstrated reduced cardiac fibrosis, improved cardiac function, and no systemic toxicity.
Conclusions:
- Engineered dendritic cells represent a promising therapeutic platform for treating cardiac remodelling and heart failure.
- Lesion-targeted immune modulation is a feasible strategy for controlling cardiac fibrosis.
- iCDC therapy offers a potential new approach to prevent or reverse heart failure progression.
Abstract:
Heart failure remains a leading cause of morbidity and mortality, yet no approved therapies effectively prevent or reverse pathological cardiac fibrosis and the associated decline in cardiac function1-4. Chronic inflammation is a central driver of pathological fibrosis after ischaemic or haemodynamic stress, but strategies that locally rebalance injurious and reparative immune responses without systemic immunosuppression are lacking5,6. Dendritic cells (DCs) are key regulators of immune activation and tolerance, providing an opportunity for therapeutic immune reprogramming in cardiac diseases7,8. Here we show that engineered immunosuppressive and fibrosis-targeted DCs (iCDCs) effectively protect against pathological cardiac remodelling. In mouse models of ischaemia-reperfusion injury, myocardial infarction and pressure overload, iCDC therapy reduced inflammatory cardiac fibrosis, improved cardiac perfusion and preserved contractility. Mechanistically, iCDCs conferred sustained cardioprotection directly by suppressing immune and stromal cell activation or indirectly through promoting clonal expansion of regulatory T cells. Importantly, in a non-human primate model of myocardial infarction, iCDC therapy also reduced cardiac fibrosis, improved cardiac perfusion and contractile function without inducing systemic toxicity. These findings establish lesion-targeted immune modulation as a feasible strategy to control cardiac fibrosis and identify engineered dendritic cells as a promising therapeutic platform for treating cardiac remodelling and heart failure.
