Cardiovascular research · 2025
CTLA-4-Ig therapy preserves cardiac function following myocardial infarction with reperfusion.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Noonan Jonathan, Prijaya Shania A, Bienvenu Laura A, Dayawansa Nalin H, Michla Marcel, Bongcaron Viktoria, Sharma Prerna, Song Yuyang, Huang Angela, Barbaro-Wahl Anastasia, Huang Yilu, Nguyen Hung, Nguyen Anne, Murphy Andrew J, Zhang Yiyu, Lee Man K S, Johnson Chad J, Watson Anna M D, Thomas Anita C, McFadyen James D, Donner Daniel G, Wang Xiaowei, Peter Karlheinz
Аннотация
AIMS: T cells drive adverse cardiac inflammation and ischemia-reperfusion injury following myocardial infarction (MI). Here, we aimed to test the extent to which T cell inhibition protected cardiac function following MI in mice.
METHODS AND RESULTS: Cardiac ischemia-reperfusion injury (CIRI), mimicking MI with successful reperfusion therapy, was induced in C57BL/6J mice via temporary surgical ligation of the left anterior descending artery. T cell inhibition was achieved using abatacept, an FDA-approved CTLA-4-Ig fusion protein. Multiple treatment strategies were assessed, ranging from prolonged treatment across 4 weeks to short-term treatment, also with delayed time-to-intervention. Cardiac function was assessed using echocardiography, including strain analysis. Impacts on the cardiac and systemic immune response were assessed using flow cytometry. CIRI-induced robust CD4+ biased T cell activation in the heart within 7 days. Treatment with abatacept significantly preserved key echocardiographic metrics of cardiac function. This treatment coincided with near-complete inhibition of the cardiac T cell response, as well as reductions in innate inflammatory cells. Collectively, this demonstrated a central mechanistic role for T cell activation post-MI with reperfusion. Evaluation of short-term intervention strategies further demonstrated sustained preservation of cardiac function even where treatment was delayed by 24 h. Mechanistically, our data indicate that over 50% of lost cardiac function post-MI with reperfusion is T cell dependent.
CONCLUSION: T cell co-stimulation leading to activation is a central driver of the cardiac immune response following MI with reperfusion. The inhibition of this axis significantly protected against CIRI and preserved cardiac function. Ultimately, we highlight T cell immunomodulation and abatacept as highly promising approaches for clinical translation.
METHODS AND RESULTS: Cardiac ischemia-reperfusion injury (CIRI), mimicking MI with successful reperfusion therapy, was induced in C57BL/6J mice via temporary surgical ligation of the left anterior descending artery. T cell inhibition was achieved using abatacept, an FDA-approved CTLA-4-Ig fusion protein. Multiple treatment strategies were assessed, ranging from prolonged treatment across 4 weeks to short-term treatment, also with delayed time-to-intervention. Cardiac function was assessed using echocardiography, including strain analysis. Impacts on the cardiac and systemic immune response were assessed using flow cytometry. CIRI-induced robust CD4+ biased T cell activation in the heart within 7 days. Treatment with abatacept significantly preserved key echocardiographic metrics of cardiac function. This treatment coincided with near-complete inhibition of the cardiac T cell response, as well as reductions in innate inflammatory cells. Collectively, this demonstrated a central mechanistic role for T cell activation post-MI with reperfusion. Evaluation of short-term intervention strategies further demonstrated sustained preservation of cardiac function even where treatment was delayed by 24 h. Mechanistically, our data indicate that over 50% of lost cardiac function post-MI with reperfusion is T cell dependent.
CONCLUSION: T cell co-stimulation leading to activation is a central driver of the cardiac immune response following MI with reperfusion. The inhibition of this axis significantly protected against CIRI and preserved cardiac function. Ultimately, we highlight T cell immunomodulation and abatacept as highly promising approaches for clinical translation.