Objective-To determine whether the administration of an active form of vitamin D 3 (calcitriol) could prevent atherosclerosis through anti-inflammatory actions. Methods and Results-Recent clinical studies have shown that lack of vitamin D 3 is a risk factor for cardiovascular events.Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4 ϩ T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3 ϩ regulatory T cells and a decrease in CD80 ϩ CD86 ϩ dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol-treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11cϩ DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell-dependent manner but also partly because of a decrease in DC maturation. , is a secosteroid hormone that not only plays a central role in bone and calcium metabolism but also modulates the immune response. Recent epidemiological studies have shown a relationship between low plasma levels of vitamin D 3 and a predisposition to cardiovascular events. [1][2][3] This finding is supported by a meta-analysis showing that oral vitamin D 3 treatment contributes to the improvement of mortality from all causes, in part by decreasing cardiovascular deaths. 4 Transgenic rats constitutively expressing vitamin D-24-hydroxylase, a model of vitamin D 3 deficiency, showed aggravated atherosclerosis under a high-fat and high-cholesterol diet, when compared with control rats. 5 However, there are no reports about the direct effects of an orally administered active form of vitamin D 3 on atherosclerosis. Conclusion-Oral See accompanying article on page 2317It is widely recognized that atherosclerosis is a complex inflammatory disease of the arterial wall, 6,7 in which the T-lymphocyte-mediated pathogenic immune response plays a critical role. Clinical strategies developed to modulate the immune response have been insufficient for preventing atherosclerosis. Cumulative data based on experimental animal models suggest that CD4 ϩ T cells are present within plaques from the initial stages of the disease in mice, and adaptive transfer of these cells is potentially proatherogenic. 8 Accumulating evidence has revealed novel functions of several subsets of regulatory T cells (Tregs), which maintain immunologic tolerance to self-antigens and inhibit atherosclerosis development by suppressing the inflammatory response of effector T cells. 9 -12 These studies have provided new insights into the immunopathogenesis of atherosclerosis and imply that promotion of regulatory immune responses may have therapeutic potential for suppression of atherosclerotic diseases.In addition to Tregs, dendritic cells (DCs) are al...

L-Kynurenine and quinolinic acid are neuroactive L-tryptophan-kynurenine pathway metabolites of potential importance in pathogenesis and treatment of neurologic disease. To identify precursors of these metabolites in brain, [ 2 H 3 ]-Lkynurenine was infused subcutaneously by osmotic pump into three groups of gerbils: controls, CNS-localized immuneactivated, and systemically immune-activated. The specific activity of L-kynurenine and quinolinate in blood, brain and systemic tissues at equilibrium was then quantified by mass spectrometry and the results applied to a model of metabolism to differentiate the relative contributions of various metabolic precursors. In control gerbils, 22% of L-kynurenine in brain was derived via local synthesis from L-tryptophan/formylkynurenine versus 78% from L-kynurenine from blood. Quinolinate in brain was derived from several sources, including: local tissue L-tryptophan/formylkynurenine (10%), blood L-kynurenine (35%), blood 3-hydroxykynurenine/3-hydroxyanthranilate (7%), and blood quinolinate (48%). After systemic immune-activation, however, L-kynurenine in brain was derived exclusively from blood, whereas quinolinate in brain was derived from three sources: blood L-kynurenine (52%), blood 3-hydroxykynurenine or 3-hydroxyanthranilate (8%), and blood quinolinate (40%). During CNS-localized immune activation, > 98% of both L-kynurenine and quinolinate were derived via local synthesis in brain. Thus, immune activation and its site determine the sources from which L-kynurenine and quinolinate are synthesized in brain. Successful therapeutic modulation of their concentrations must take into account the metabolic and compartment sources.

In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence.

Although regulatory T cells (Tregs) have been shown to play a protective role in abdominal aortic aneurysm (AAA) formation, it remains unclear whether expansion of endogenous Foxp3 + Tregs prevents AAA. In the current study, we determined the effects of endogenous Foxp3 + Treg expansion or depletion in an experimental model of AAA. We continuously infused 12-week-old apolipoprotein E–deficient mice fed a high-cholesterol diet with angiotensin II (n=60) or normal saline (n=12) by implanting osmotic mini-pumps and evaluated AAA formation at 16 weeks. The angiotensin II–infused mice received interleukin-2/anti–interleukin-2 monoclonal antibody complex (interleukin-2 complex; n=31) or PBS (n=29). Eighty-one percent of angiotensin II–infused mice developed AAA, with 42% mortality possibly because of aneurysm rupture. Interleukin-2 complex treatment systemically increased the number of Foxp3 + Tregs and significantly decreased the incidence (52%) and mortality (17%) of AAA. Immunohistochemical analysis showed reduced accumulation of macrophages and increased numbers of Foxp3 + Tregs in aneurysmal tissues, suggesting that expansion of Tregs may suppress local inflammation in the vessel wall and provide protection against AAA formation. Furthermore, genetic depletion of Foxp3 + Tregs led to a significant increase in the mortality of AAA, suggesting the protective role of Foxp3 + Tregs against AAA. Our findings suggest that Foxp3 + Tregs may play a protective role in AAA formation and that promotion of an endogenous regulatory immune response may be a potentially valuable therapeutic approach for preventing AAA.