Vaccination and Atherosclerosis Xinghua Zhou, MD, PhD, and Göran K. Hansson, MD, PhD Address Center for Molecular Medicine L8:03, Karolinska Hospital, Karolinska Institutet, S-17176 Stockholm, Sweden. E-mail: Xinghua.Zhou@cmm.ki.se Current Atherosclerosis Reports 2004, 6:158–164 Current Science Inc. ISSN 1523–3804 Copyright © 2004 by Current Science Inc. Introduction Vaccination originally referred to a phenomenon in which the infection with a bovine analogue of smallpox, vaccinia, stimulated an immune response that cross-reacts with smallpox and thereby conferred protection from the human form of the disease. The term has been further extended to the induction of immunoprotection to other infectious agents. Vaccination has been a very effective way of controlling infectious diseases over the past 200 years, virtually eliminating several human lethal diseases such as diphtheria, polio, and measles in the Western world. Atherosclerosis is characterized by patchy subintimal thickenings of medium and large arteries, which reduce or obstruct blood flow and lead to myocardial infarction, cerebral infarction, aortic aneurysm, and peripheral vascular diseases. As a consequence, atherosclerosis remains the principal cause of death in the Western world and much of Asia. In recent years, the pathogenesis of atherosclerosis has been revealed to be related not only to cholesterol deposition, macrophage infiltration, and smooth muscle cell (SMC) proliferation in the lesions, but also systemic and local innate and adaptive immune responses [1••,2••]. The first line of immune defense is dependent on detec- tion of pathogen-associated molecular patterns (PAMPs), which evoke an inflammatory response. These PAMPs include endotoxin/lipopolysaccharides (LPS), lipoteichoic acid, heat shock proteins (HSPs), peptide glycans, and prokaryotic DNA motifs, which can all be recognized by the scavenger and Toll-like receptors on macrophages. Such a ligation leads to endocytosis and lysosomal degradation of the PAMP-coated particles and activates nuclear factor κB (NF-κB) signaling pathway in phagocytes [3]. Importantly, pattern recognition receptors, including scavenger receptors (SRs) and probably also Toll-like receptors (TLRs), bind oxi- datively modified low-density lipoprotein (LDL) particles [4–6]. LDL modification, therefore, generates PAMP and elicits innate immune responses. Studies have further indicated that the initiation of atherosclerosis can be viewed as a response of the innate immune system to the accumula- tion and modification of lipoprotein in the intima. Indeed, lack of scavenger receptor A (SR-A) or CD36 through gene- knockout technique in vivo decreases the development of atherosclerosis in murine models [7,8]. T cells, which are key representatives of adaptive immu- nity, also participate in the formation of atherosclerosis as early as monocytes and macrophages [9•]. Atherosclerotic lesions contain significant amounts of activated T cells, with the expression of T-cell cytokines such as interferon γ (IFNγ ) and of cytokine-induced genes like HLA-DR in the lesions [10,11]. The expression of HLA-DR by activated macrophages and activated T cells adjacent to these mac- rophages in the lesions strongly suggests that a cell- mediated immune reaction is taking place in the process of atherosclerosis. Lack of IFNγ or its receptor as well as com- plete lack of adaptive immunity in murine models leads to less lesion formation [12–15], whereas T-cell transfer or direct IFNγ injection exaggerates atherosclerosis [13,16]. Although a minority of lymphocytes in human plaques bears markers for B cells, mRNA expression of κ-chain was detected in the lesions of animal model [17]. High-titer autoantibodies, produced by activated B cells and specific to oxidized (ox) LDL, have been found in circulation and lesions of humans and hypercholesterolemic animal models [18,19]. Furthermore, complement factors such as C1 and C3b, terminal C5b-9 complement complex, and complement receptors have also been found in human and animal lesions. These findings suggest that activation of humoral immune responses is also involved in the disease process [20,21]. The findings that removal of B cells via splectomy enhances lesion formation whereas polyclonal Atherosclerosis is an inflammatory disease. Both innate and adaptive immunity are involved in lesion formation and development. A number of antigen candidates, such as oxidized low-density lipoprotein and heat shock protein, have been associated with the inflammation and immune reaction that is part of the atherosclerotic process. Because experimental models of some other inflammatory/ autoimmune diseases can be improved by vaccination, it is of interest to investigate if vaccination can also be applied to prevent or retard atherosclerosis. Indeed, the modification of immune responses in animal models can greatly affect the development and progression of atherosclerosis. This review provides an overview of our current understanding of effects and proposed mechanisms of immunization on preventing atherosclerosis.