Title: The effect of low-dose interleukin-2 on atherosclerotic plaque immune cells in patients undergoing carotid endarterectomy
Funder: The Academy of Medical Sciences

Abstract: My proposal aims to assess the immune-modulating effect of administering low-dose interleukin-2 (ld-IL-2) on patient carotid plaque immune cells, and particularly regulatory T-cells (Tregs). To achieve this, we propose to recruit patients before their elective carotid endarterectomy and randomise them to either ld-IL-2 treatment or control until their surgery. Carotid plaques obtained at surgery will be analysed using single-cell RNA-sequencing (scRNA-seq) experiments to study the effect of ld-IL-2 compared to control. Atherosclerosis is an immune-mediated disease characterised by chronic inflammation. Tregs are essential for maintaining immune tolerance. Preclinical models have shown that Tregs decrease atherosclerotic plaque progression and promote myocardial healing. Furthermore, patients with ischaemic heart disease (IHD) have reduced Tregs and increased pro-inflammatory effector T-cells (Teffs). Ld-IL-2 administration selectively increases Treg cells in patients with autoimmune diseases. We recently completed a phase 1/2a randomised, placebo-controlled, double-blind, clinical trial and showed that ld-IL2 is safe and well-tolerated in patients with IHD and myocardial infarction. We found an effective dose of ld-IL-2 which increased blood levels of Tregs without increasing Teffs. Using scRNA-seq of peripheral blood mononuclear cells, we showed an increased number and suppressive function of Tregs after treatment. However, whether changes in blood Treg cells are mirrored in plaques, and therefore able to directly affect the pathophysiology of atherosclerosis, is unknown. If successful, this will be an important step in the translation of this therapy to phase 3 clinical testing. Furthermore, it will have broader implications for the use of new techniques like scRNA-seq in guiding cardiovascular drug development.

Lay abstract: Narrowing of the blood vessels causes reduced blood flow to important organs like the heart and brain, which for sufferers, results in chest tightness on exertion (angina), heart attacks, and strokes. The narrowings are caused by a disease process called atherosclerosis and, despite medical advances, is the leading cause of deaths globally and can lead to long-term disability. Atherosclerosis is due to a combination of fatty deposits within the blood vessel walls and the immune system’s long-term reaction to the deposits called inflammation. However, we still do not have any successful treatments to target this inflammation. In our previous clinical trial, we successfully used low doses of interleukin-2, an important messenger hormone, in patients with heart attacks to increase a group of immune cells that suppress inflammation. In animal models, this leads to reduced atherosclerosis, heart attacks, and strokes. Whether interleukin-2 can have the same effect in patients is currently unknown. To help us investigate this, we propose to give interleukin-2 to patients before their planned surgery to remove their blood vessel narrowings in their neck blood vessel, which is a normal clinical procedure. We will then examine these removed narrowings using state-of-the-art techniques to assess if interleukin-2 is having the desired effects of reducing inflammation and disease progression. If successful, this will be an important step towards developing interleukin-2 into a potential treatment to help patients live longer and healthier lives. Furthermore, this unique and innovative technique could be used in the future to develop other drugs.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR