Regulatory T Cell-Enhancing Therapies to Treat Atherosclerosis

Abstract

Experimental studies have provided strong evidence that chronic inflammation triggered by the sub-endothelial accumulation of cholesterol-rich lipoproteins in arteries is essential in the initiation and progression of atherosclerosis. Recent clinical trials highlighting the efficacy of anti-inflammatory therapies in coronary patients have confirmed that this is also true in humans Monocytes/macrophages are central cells in the atherosclerotic process, but adaptive immunity, through B and T lymphocytes, as well as dendritic cells, also modulates the progression of the disease. Analysis of the role of different T cell subpopulations in murine models of atherosclerosis identified effector Th1 cells as proatherogenic, whereas regulatory T cells (Tregs) have been shown to protect against atherosclerosis. For these reasons, better understanding of how Tregs influence the atherosclerotic process is believed to provide novel Treg-targeted therapies to combat atherosclerosis. This review article summarizes current knowledge about the role of Tregs in atherosclerosis and discusses ways to enhance their function as novel immunomodulatory therapeutic approaches against cardiovascular disease.

Vaccination against Atherosclerosis: Is It Real?

“…Thus, it would not be expected to cause the small increase in frequency of fatal infections of the kind observed in the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial [ 50 ]. Mucosal administration of apoB peptides, as well as subcutaneous injection of apoB peptides with or without aluminum-based adjuvants, have all been shown to inhibit atherosclerosis in experimental models through the activation of Tregs [ 53 , 54 , 55 ]. Data on animal studies targeting various antigens are summarized in Table 1 .…”

Mechanistic Insight into PPARγ and Tregs in Atherosclerotic Immune Inflammation

“…The relationship between the degree of immune inflammatory response and AS has been most widely studied. There is evidence that Tregs inhibit the expression of pro-inflammatory IFN-γ, IL-4, IL-17, IL-6, and chemokines secreted by Th1, Th2, and Th17 in atherosclerotic plaques through the release of TGF-β and IL-10 ( Albany et al, 2019 ; Ait-Oufella et al, 2021 ), which exert anti-AS effects.…”

Immunotherapeutic Strategies in Cancer and Atherosclerosis—Two Sides of the Same Coin

“…Although prevention strategies and therapeutic opportunities have been significantly improved during the past decades, atherosclerotic cardiovascular diseases (CVD) and cancer still represent the two most common causes of death worldwide (1). As already recognized by Rudolph Virchow in the nineteenth century (2,3), the critical role of inflammatory processes in atherogenesis and carcinogenesis is now well-established and has prompted investigation of strategies to combat these deadly diseases by modulating underlying immune responses (4)(5)(6)(7)(8)(9)(10). Several anti-cancer immunotherapies, such as cytokines, antibodies targeting immune cell receptors, or immune checkpoints, dendritic cell therapy, and chimeric antigen receptor (CAR) T cell therapy, already found their way into clinical practice and thereby revolutionized cancer treatment (9,11).…”

“…CANTOS illustrated the central dilemma of many immunomodulatory strategies: Broad interventions in the immune system can have detrimental side effects. In general, anti-atherosclerotic strategies are geared toward suppression of vascular inflammation ( 5 , 8 , 15 ), whereas immune-based cancer treatments aim at enhancing immune responses against tumor cells ( 7 , 9 ). The therapeutic efficacy of several anti-cancer immunotherapies is constrained by their proimmunogenic (and thus proatherogenic) properties, increasing the risk to develop CVD in patients ( 16 ).…”