Therapeutic modulation of the adaptive immune response in atherosclerotic cardiovascular disease: bridging clinical translation

A maladaptive immune response plays a crucial role in atherosclerosis progression, yet there are no approved therapies targeting this area. We have shown that low-doses of interleukin-2 (ld-IL-2) can increase anti-inflammatory regulatory T cells in patients with ischaemic heart disease (LILACS trial) and reduce vascular inflammation on PET/CT imaging (IVORY trial). However, to gain mechanistic insight and progress this treatment further to a phase 3 clinical trial, several knowledge gaps need addressing. Firstly, we will perform single-cell RNA-sequencing on blood taken from patients in the IVORY trial to provide a deeper understanding of the immune response after acute myocardial infarction and the effect of ld-IL-2 on the whole immune landscape and specifically T cells. Secondly, the adaptive immune system is defined by an antigen-specific response however, this remains largely unaddressed. We will use high-throughput single-T-cell receptor sequencing to provide a detailed view of the immune receptor landscape and combine in-silico with animal models to study antigen specificity. Lastly, leveraging the unique IVORY trial, where treatment with a targeted anti-inflammatory drug has decreased vascular inflammation, we will use a broad proteomic approach to study mechanisms and discover biomarkers that can predict treatment response and be used more readily during clinical care.