Readapting the adaptive immune response – therapeutic strategies for atherosclerosis

Abstract

Cardiovascular diseases remain a major global health issue, with the development of atherosclerosis as a major underlying cause. Our treatment of cardiovascular disease has improved greatly over the past three decades, but much remains to be done reduce disease burden. Current priorities include reducing atherosclerosis advancement to clinically significant stages and preventing plaque rupture or erosion. Inflammation and involvement of the adaptive immune system influences all these aspects and therefore is one focus for future therapeutic development. The atherosclerotic vascular wall is now recognized to be invaded from both sides (arterial lumen and adventitia), for better or worse, by the adaptive immune system. Atherosclerosis is also affected at several stages by adaptive immune responses, overall providing many opportunities to target these responses and to reduce disease progression. Protective influences that may be defective in diseased individuals include humoral responses to modified LDL and regulatory T cell responses. There are many strategies in development to boost these pathways in humans, including vaccine‐based therapies. The effects of various existing adaptive immune targeting therapies, such as blocking critical co‐stimulatory pathways or B cell depletion, on cardiovascular disease are beginning to emerge with important consequences for both autoimmune disease patients and the potential for wider use of such therapies. Entering the translation phase for adaptive immune targeting therapies is an exciting and promising prospect. Linked Articles This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc

B Cell–Mediated Antigen Presentation through MHC Class II Is Dispensable for Atherosclerosis Progression

“…Despite adaptive immunity being implicated in murine models of atherosclerotic disease since the early 1990s, little is understood in terms of where Ag presentation occurs or which cells are responsible for cognate interactions with T cells. Targeting the adaptive immune system for therapeutic intervention of high-risk patients has been gaining momentum and may be more feasible than broadly targeting the innate immune system (25).…”

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

“…Moreover, local release of cholesterol crystals activates the inflammasome, generating active IL‐1β and triggering pro‐inflammatory signalling (Freigang et al, ). In addition to the direct actions of pro‐inflammatory mediators on macrophage phenotype, mast cell degranulation, dysregulation of T cell subsets, B‐cell‐derived cytokine synthesis and stimulation of vascular cells in the plaque environment have also been implicated in activation of inflammatory macrophages in atherosclerotic plaques (Kaartinen et al, ; Mazzolai et al, ; Tay et al, ; Sage and Mallat, ; Tabas and Lichtman, ).…”

Cytokines at the Interplay Between Asthma and Atherosclerosis?

“…Th1 and Th17-type responses have also been shown to play a role in asthma pathogenesis, and elevated levels of IFN-g, TNFa, and IL-17A can be found in the serum of asthmatic patients. This is of particular interest as Th1 and Th17 type responses are more characteristically associated with atherosclerosis (Sage and Mallat, 2017). It should be noted, however, that several of these mediators have also been shown to be produced by mast cells in asthma (Kennedy et al, 2013).…”

“…IL-10 deficiency significantly augments the development of atherosclerotic lesions in hyperlipidemic low-density lipoprotein receptor (LdlR) −/− mice and also accelerates neointimal formation in hypercholesteremic ApoE*3-Liden mice (Potteaux et al, 2004;Eefting et al, 2007). Similarly, Tregs have been shown to be clearly protective in experimental atherosclerosis (Sage and Mallat, 2017), and two clinical trials are currently investigating the possibility to promote Treg expansion in patients with small abdominal aortic aneurysms (VIVAAA; ClinicalTrials.gov Identifier: NCT02846883), or with stable ischemic heart disease and acute coronary syndromes (LILACS; ClinicalTrials.gov Identifier: NCT03113773).…”