Objective-Atherosclerosis is associated with immune responses to oxidized low-density lipoprotein (oxLDL). The presence of activated macrophages and T cells in lesions suggests that cell-mediated immune reactions are taking place during the disease process. However, the role of specific immune responses has remained unclear. We have previously shown that transfer of CD4 ϩ T cells from apolipoprotein E knockout mice (apoE Ϫ/Ϫ ) into immunodeficient apoE Ϫ/Ϫ scid/scid mice accelerates disease. Methods and Results-To test whether this effect is dependent on specific disease-associated antigens, purified CD4 ϩ T cells from oxLDL-immunized mice were transferred into apoE Ϫ/Ϫ scid/scid mice. CD4 ϩ T cells from mice immunized with a nonrelevant antigen, keyhole limpet hemocyanin (KLH), and naïve CD4 ϩ T cells were used as controls. After 12 weeks, all mice that received T cells had larger lesions than untouched apoE Ϫ/Ϫ scid/scid controls. However, mice receiving CD4 ϩ T cells from oxLDL immunized mice had substantially accelerated lesion progression compared with those receiving naive or KLH-primed T cells. Circulating levels of interferon-␥ were increased in proportion to the acceleration of atherosclerosis. Conclusion-These data show that adoptive transfer of purified CD4ϩ T cells from oxLDL-immunized mice accelerates atherosclerosis. They support the notion that Th1 cellular immunity is proatherogenic and identify oxLDL as a culprit autoantigen. Key Words: atherosclerosis Ⅲ lymphocytes Ⅲ low-density lipoprotein Ⅲ immune system Ⅲ mice, knockout Ϫ/Ϫ R esearch over the last decades has identified immune mechanisms as pathogenically important in atherosclerosis. 1,2 T lymphocytes and macrophages are present in lesions throughout the development of disease, both in man and experimental models. [3][4][5][6] Most of the T cells in the lesions are CD4ϩ TCRab ϩ T cells expressing activation markers such as human leukocyte antigen-DR (HLA-DR) and interferon-␥ (IFN-␥). 3,4,[7][8][9] The expression of major histocompatibility complex (MHC) class II molecules such as HLA-DR on activated macrophages and activated T cells adjacent to these macrophages in the lesions strongly suggests that cellmediated immune reactions are taking place in atherosclerosis.A series of investigations have suggested modified low density lipoproteins (LDLs) as autoantigens in atherosclerosis. 10 LDL accumulates in lesions, where it is modified by oxidative and enzymatic processes. [11][12][13][14][15] Circulating autoantibodies to epitopes of oxidized LDL (oxLDL) have been detected in patients and experimental animals with atherosclerosis, 13,16 and antibodies isolated from atherosclerotic lesions recognize oxLDL. 17 Macrophages can take up, process, and present neoantigens such as oxLDL to CD4ϩ T cells, eliciting cellular immune responses. 18 Indeed, Ϸ10% of the CD4ϩ T cells cloned from human lesions recognize oxLDL in an MHC class II-dependent manner. 9 The apolipoprotein E knockout (apoE Ϫ/Ϫ ) mouse is a useful model of human disease because it deve...

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Abstract. Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe -/-mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl 2 -induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta.

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