A Vaccine Against Atherosclerosis: Myth or Reality?

Gijs HM van Puijvelde; Thomas van Es; Kim LL Habets; Arnaud D Hauer; Theo JC van Berkel; Johan Kuiper

Disclosures

Future Cardiol. 2008;4(2):125-133. 

In This Article

Abstract and Introduction

Atherosclerosis is a chronic inflammatory disease that develops in the context of enhanced serum lipid levels. Nowadays, many studies focus on the modulation of inflammatory responses to reduce atherosclerosis. The most powerful strategy to achieve this is vaccination. In several immune diseases vaccination is shown to be very effective, resulting in a drastic decline in the incidence of the disease. But is vaccination also realistic in atherosclerosis? In this article, several approaches to vaccinate against atherosclerosis are described. Vaccination (based on protein or DNA) against bioactive molecules and disease-related proteins successfully reduces experimental atherosclerosis. In addition, passive immunization with antibodies against atherosclerosis-specific antigens and tolerance induction, in which antigen-specific regulatory T cells are elicited, are described. In the near future, we expect an increased interest in vaccination against atherosclerosis and, maybe, the myth may become reality when the first clinical trials are performed.

Atherosclerosis, the main underlying pathology of cardiovascular disease, is a multifactorial, chronic, autoimmune-like disease initiated by both lipid accumulation and inflammatory processes.[1–3] Both the innate immune response, represented by monocytes and macrophages, and adaptive immune responses, represented by T and B cells, are important in the onset and progression of atherosclerosis. The modification of lipoproteins and the subsequent activation of endothelial cells results in an increased expression of chemokines and adhesion molecules, leading to the attraction of monocytes and subsequent diapedesis into the vessel wall. The monocytes ingest the modified lipoproteins and differentiate into foam cells. These foam cells produce chemokines and cytokines that enhance the recruitment of more monocytes and also T cells, thereby aggravating atherosclerosis. Dendritic cells are pivotal in bridging the innate and the adaptive immune responses, and the switch towards an adaptive immune response is considered to be of utmost importance in the development of autoimmune diseases. Locally (within the lesion), but also systemically (periphery), dendritic cells ingest autoantigens such as oxidatively modified-LDL (ox-LDL) and heat-shock proteins (HSPs), and migrate to secondary lymphoid organs – the spleen and draining lymph nodes – where they will activate both naive and antigen-specific T cells. Subsequently, the T cells migrate towards the atherosclerotic lesion. These effector T cells mainly produce T helper (Th)1-associated cytokines such as IL-12, IFN-ϒ, IL-6 and IL-1ß within the lesion, which are proatherogenic and lead to enhanced activation and recruitment of T cells, macrophages and dentric cells in the plaque. A disturbed balance between Th-1 and -2 cytokines has long been suggested as the underlying cause of the autoinflammatory pathology in atherosclerosis. Th2 cytokines such as IL-5 and -10 are antiatherogenic and may counteract the Th1 cytokines.[1–3] During recent years, this theory has been challenged by a new hypothesis in which regulatory T cells (Tregs) play a pivotal role, since they can dampen inflammatory responses in several autoimmune diseases. Therefore, Tregs may hold promise in the future treatment of atherosclerosis.[3,4]

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