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Abstract-Atherosclerosis is an inflammatory disease, and the involvement of immune mechanisms in disease progression is increasingly recognized. Immunization with oxidized low density lipoprotein (LDL) decreases atherosclerosis in several animal models. To explore humoral and cellular immune reactions involved in this protection, we immunized apolipoprotein E knockout mice with either homologous plaque homogenates or homologous malondialdehyde (MDA)-LDL. Immunization with both these antigen preparations reduced lesion development. The plaques contained immunogen(s) sharing epitopes on MDA-LDL, MDA-very low density lipoprotein, and oxidized cardiolipin. This shows that a T-cell-dependent antibody response was associated with protection against atherosclerosis. The protection was associated with specific T-cell-dependent elevation of IgG antibodies against MDA-LDL and oxidized phospholipids, and the increased titers of IgG antibodies were correlated with decreased lesion formation and lower serum cholesterol levels.

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Sweden CTLA-4 is an important negative regulator of the immune system. The regulation of the CTLA-4 gene (Ctla-4) transcription is poorly understood. A single nucleotide polymorphism (SNP) at −318 in the Ctla-4 promoter region is associated with certain autoimmune diseases. Since the −318 SNP occurs in a potential regulatory region, it is conceivable that the CЈ T transition may affect the expression of In the present study, we show that the −318T allele is associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49 CTLA-4 plays an important role in the immune system as a T cell inhibitory factor. This inhibitory signal not only determines whether T cells become activated, but also affects the clonal representation in an immune response. CTLA-4 regulates cell cycle progression rather than directly the induction of apoptosis. 1 CTLA-4 Ig and anti-CTLA-4 have been applied for the treatment of both autoimmune diseases and cancers.Little is known about the regulatory mechanism for CTLA-4 expression. Polymorphisms in the Ctla-4 are associated with several autoimmune diseases, and polymorphisms at certain locations of the Ctla-4 might conceivably affect its expression. We have described a higher prevalence of thymine at position −318 of the Ctla-4 promoter (−318T) in patients with Wegener's granulomatosis. 2 Recently, Ligers and colleagues reported that individuals carrying −318T exhibited significantly increased expression both of cell-surface CTLA-4 in activated cells and of Ctla-4 mRNA in non-stimulated cells, 3 suggesting a potential role for the CЈ T transition in the regulation of expression. In the present study, we examined the effect of CЈ T switch at −318 on the Ctla-4 promoter activity. Our results demonstrated that the −318T allele was associated with a significantly higher promoter activity than the −318C allele. Results and discussionTo determine whether the CЈ T transition at position −318 transcriptionally regulates the Ctla-4 gene expression, we made two Ctla-4 promoter reporter constructs which contained C and T alleles, respectively. As shown in Figure 1, the −318T allele was associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49). This result was also confirmed in the THP-1 cell line transfected with these two reporter constructs, and stimulated with IFN-␥ (5 mg/ml) and PMA (10 ng/ml).Our allele-specific transcription data indicate that the −318T allele is associated with higher transcriptional activity than the −318C allele. The -318T allele could be considered as protective against autoimmune reactions. Our results could explain the increased expression of CTLA-4 3 and the observed associations of the −318T allele to some diseases. 4 Homozygosity for −318/T in the promoter of Ctla-4 is rarely present in a Caucasian population. [4][5][6][7] In our previous study, the frequencies of individuals with genotypes −318C/C, C/T, and T/T were 86%, 17% and 0%, respectively, in healthy individuals (n = 122) and 69%, 31%, 0%, respective...

Oxidation and scavenger receptor-mediated uptake of low density lipoprotein (LDL) in intimal macrophages are believed to be key events in the development of atherosclerosis. We report here that oxidized LDL increases DNA synthesis, expression of HLA-DR, and interleukin-2 receptors in T cells. The stimulatory effect of oxidized LDL was not due to a direct effect on T cells but required the presence of monocytes. Oxidized LDL also stimulated the release of interleukin-10 from monocytes. The maximal effect of oxidized LDL on T-cell activation and interleukin-1/3 release occurred at a concentration of 1 figjml. Native LDL also had the capacity to activate T cells, although only at higher concentrations. The stimulatory effect of both native and oxidized LDL was inhibited by superoxide dismutase. Monocytes as well as T cells were found to have the ability to oxidize LDL, suggesting that the stimulatory effect of native LDL may arise as a result of LDL oxidation during incubation with monocytes and T cells. The results suggest that oxidized LDL may activate T ceils in atherosclerotic lesions. (Arteriosclerosis and Thrombosis 1992;12:461-467)