Vaccination in Atherosclerosis

Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number of actionable targets whose clinical exploration will help achieve the goal of optimizing beneficial effects while avoiding undue interference with host defenses or other unwanted actions. This review aims to furnish the foundation for this quest by critical evaluation of the current state of anti-inflammatory interventions within close reach of clinical application, with a primary focus on innate immunity. In particular, this paper highlights the pathway from the inflammasome, through interleukin (IL)-1 to IL-6 supported by a promising body of pre-clinical, clinical, and human genetic data. This paper also considers the use of biomarkers to guide allocation of anti-inflammatory therapies as a step toward realizing the promise of precision medicine. The validation of decades of experimental work and association studies in humans by recent clinical investigations provides a strong impetus for further efforts to target inflammation in atherosclerosis to address the considerable risk that remains despite current therapies.

Section: Targeting Adaptive Immune Responsesmentioning

confidence: 99%

Targeting Inflammatory Pathways in Cardiovascular Disease: The Inflammasome, Interleukin-1, Interleukin-6 and Beyond

Libby

2021

“…Since 1959, when Gero et al performed the first atheroprotective vaccination of rabbits with LDL [ 224 ], numerous studies in rodents have demonstrated that vaccination with either native, modified (oxidized) LDL, or (peptides from) ApoB has the potential to elicit a T-cellular immune response that prevents atherosclerosis [ 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 ]. ApoB-100 and its truncated version, ApoB-48, which is present in chylomicrons [ 235 ], contain several immunogenic T cell peptide epitopes.…”

Section: Function Of Apob-specific Cd4 + T Cellmentioning

confidence: 99%

“…However, the limitations of unspecific anti-inflammatory treatments remain considerable as evidenced by increased rates of infection and missing experience on long-term treatments. By contrast, the development of antigen-specific immunomodulation holds the promise of specific antigen-directed therapies with only minimal side-effects [ 234 ]. The recent development of technologies to detect ApoB-specific T cells at the single cell level, including MHC-class II tetramers, has greatly widened our understanding of adaptive immune mechanisms in atherosclerosis [ 25 ].…”

Section: Clinical Translation and Outlookmentioning

confidence: 99%

ApoB-Specific CD4+ T Cells in Mouse and Human Atherosclerosis

Marchini

Hansen

Wolf

2021

Atherosclerosis is a chronic inflammatory condition of the arterial wall that leads to the formation of vessel-occluding plaques within the subintimal space of middle-sized and larger arteries. While traditionally understood as a myeloid-driven lipid-storage disease, growing evidence suggests that the accumulation of low-density lipoprotein cholesterol (LDL-C) ignites an autoimmune response with CD4+ T-helper (TH) cells that recognize self-peptides from Apolipoprotein B (ApoB), the core protein of LDL-C. These autoreactive CD4+ T cells home to the atherosclerotic plaque, clonally expand, instruct other cells in the plaque, and induce clinical plaque instability. Recent developments in detecting antigen-specific cells at the single cell level have demonstrated that ApoB-reactive CD4+ T cells exist in humans and mice. Their phenotypes and functions deviate from classical immunological concepts of distinct and terminally differentiated TH immunity. Instead, ApoB-specific CD4+ T cells have a highly plastic phenotype, can acquire several, partially opposing and mixed transcriptional programs simultaneously, and transit from one TH subset into another over time. In this review, we highlight adaptive immune mechanisms in atherosclerosis with a focus on CD4+ T cells, introduce novel technologies to detect ApoB-specific CD4+ T cells at the single cell level, and discuss the potential impact of ApoB-driven autoimmunity in atherosclerosis.

“…The induction of antigen-specific immunological tolerance has the potential to inhibit harmful immune responses to self- or allogeneic antigens, while preserving the integrity of the remaining immune system. Different strategies of immunization with LDL, oxLDL, or ApoB-related peptides have proved beneficial in experimental models of atherosclerosis [ 96 ]. Unexpected observations of reduced atherosclerosis in hypercholesterolemic rabbits immunized with oxLDL were the first indications that it could be possible to use a “vaccine” approach to treat atherosclerosis [ 97 , 98 ].…”

Section: Strategies To Promote Atheroprotective T Cell Immunitymentioning

confidence: 99%

Regulatory T Cell-Enhancing Therapies to Treat Atherosclerosis

Ait‐Oufella

Lavillegrand

Tedgui

2021

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.