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Objective: The proatherogenic effect of IL-18 is shown to be dependent on IFN-gamma production. It is believed that activated T cells play a proatherogenic role through secretion of IFN-gamma. However, recent studies in vitro have shown that macrophages, NK cells, and even vascular smooth muscle cells may also secrete IFN-gamma after stimulation by cytokines like IL-18. We therefore investigated whether cells other than activated T cells can play a proatherogenic role via IFN-gamma secretion under the stimulation of IL-18 in vivo., Methods and Results: SCID/apoE knockout mice were injected intraperitoneally with either IL-18 or phosphate-buffered saline 3 times per week for 7 weeks. Our results show that administration of IL-18 leads to 3-fold larger lesions and 2-fold higher circulating IFN-gamma despite the absence of T cells. In addition, increased IFN-gamma, accompanied by elevation of the scavenger receptor/chemokine CXCL16, was observed in both lesions and spleens. Furthermore, our findings revealed that macrophages, NK cells, and vascular cells were the source of IFN-gamma under the stimulation of IL-18 in the absence of T cells in vivo., Conclusions: The current data suggest that the proatherogenic effect of IL-18 can occur in the absence of T cells and that IFN-gamma secreted by macrophages, NK cells, and vascular cells is sufficient for the disease progression.

Atherosclerosis is a complex disease, bearing many of the characteristics of a chronic inflammatory process. Both cellular and humoral immune responses may be involved in the disease development. Oxidized low-density lipoprotein (oxLDL) is suggested to be an autoantigen in atherosclerosis. A protective effect against atherosclerosis has been demonstrated in animals immunized with oxLDL. Such a protection is associated with elevation of T cell-dependent IgG antibodies against oxLDL. In addition, it has been shown that immunization with Freund adjuvant alone also confers protection against development of atherosclerosis. We therefore hypothesized that CD4+ T cells are critical in the development of atherosclerosis and that they are involved in protective immune reactions after immunization. The development of atherosclerosis was studied in apolipoprotein E knockout (apoE KO) mice and CD4/apoE double knockout (dKO) mice that were immunized with either oxLDL in Freund adjuvant or adjuvant alone, or left untreated. Our results show that (1) the absence of CD4+ cells in apoE KO mice leads to reduced atherosclerosis, indicating that CD4+ cells constitute a major proatherogenic cell population, and (2) the atheroprotective effect of LDL immunization does not depend on CD4+ cells, whereas (3) the atheroprotective effect of adjuvant injection is CD4-dependent. These findings demonstrate complex roles of immune cell-cell interactions in the regulation of the atherosclerotic process and point to several possible targets in the treatment and prevention of atherosclerosis.

During the last few decades, the pathogenesis of atherosclerosis has been related not only to cholesterol deposition and cell proliferation in the lesions, but also to infiltration of immune cells, which are involved in both systemic and local, innate as well as adaptive, immune responses. A number of antigen candidates, such as oxidised low-density lipoprotein and heat-shock proteins, have been associated with the disease process. As some inflammatory and autoimmune diseases could be treated by immunologically based therapy, it is of particular interest whether such principles can also be applied to prevent or treat atherosclerosis. Indeed, modification of immune reactions in animal models can greatly affect the development and progression of atherosclerosis. This review provides an overview of our current understanding of how immunomodulation changes the course of atherosclerosis and how vaccination may be used for preventing the disease.

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.

Increasing evidence suggests that atherosclerosis is an inflammatory disease promoted by hypercholesterolemia. The role of adaptive immunity has been controversial, however. We hypothesized that proatherogenic T cells are controlled by immunoregulatory cytokines. Among them, TGF-beta has been implied in atherosclerosis, but its mechanism of action remains unclear. We crossed atherosclerosis-prone ApoE-knockout mice with transgenic mice carrying a dominant negative TGF-beta receptor II in T cells. The ApoE-knockout mice with disrupted TGF-beta signaling in T cells exhibited a sixfold increase in aortic lesion surface area, a threefold increase in aortic root lesion size, and a 125-fold increase in aortic IFN-gamma mRNA when compared with age-matched ApoE-knockout littermates. When comparing size-matched lesions, those of mice with T cell-specific blockade of TGF-beta signaling displayed increased T cells, activated macrophages, and reduced collagen, consistent with a more vulnerable phenotype. Ab's to oxidized LDL, circulating T cell cytokines, and spleen T cell activity were all increased in ApoE-knockout mice with dominant negative TGF-beta receptors in T cells. Taken together, these results show that abrogation of TGF-beta signaling in T cells increases atherosclerosis and suggest that TGF-beta reduces atherosclerosis by dampening T cell activation. Inhibition of T cell activation may therefore represent a strategy for antiatherosclerotic therapy.

Atherosclerosis is an inflammatory disease. T lymphocytes, occurring concomitantly with macrophages, are found in atherosclerotic lesions with substantial numbers in all stages. Most of the T cells in the lesions are CD4(+) T cells. The finding of activated T cells and macrophages in lesions and cloning of T cells specific for modified low-density lipoproteins from lesions suggest that a cell-mediated immune reaction is taking place in atherosclerosis. This review provides an overview of our current understanding of the roles of CD4(+) T cell subpopulations in atherosclerosis.

Atherosclerosis is an inflammatory disease elicited by a lipid metabolic disturbance at sites of hemodynamic strain. Careful clinical and histopathological studies in humans as well as investigations in experimental models have identified all these phenomena, i.e. inflammation, metabolism, and hemodynamics, as playing key roles in the initiation and progression of atherosclerotic cardiovascular disease. While in-depth research into the regulation of cholesterol metabolism and blood pressure has led to new therapies against atherosclerotic cardiovascular diseases, our understanding of the inflammatory component of atherosclerosis remains incomplete and will require further research before new therapeutic or preventive strategies can be developed. This brief review will discuss new data regarding the regulation of proatherosclerotic, adaptive immunity, which is a strong driving force for the inflammatory process in the atherosclerotic plaque. [Copyright &y& Elsevier]