This Article Full Text Full Text (PDF) All Versions of this Article: 104/12/e62    most recent CIRCRESAHA.109.196667v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wigren, M. Articles by Nilsson, J. PubMed PubMed Citation Articles by Wigren, M. Articles by Nilsson, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ALUMINUM HYDROXIDE ALUMINUM SULFATE ALUM, POTASSIUM Related Collections Other arteriosclerosis Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors

(Circulation Research. 2009;104:e62.)
© 2009 American Heart Association, Inc.

UltraRapid Communication

Atheroprotective Effects of Alum Are Associated With Capture of Oxidized LDL Antigens and Activation of Regulatory T Cells

Maria Wigren, Daniel Bengtsson, Pontus Dunér, Katarina Olofsson, Harry Björkbacka, Eva Bengtsson, Gunilla Nordin Fredrikson, Jan Nilsson

From the Department of Clinical Sciences (M.W., D.B., P.D., K.O., H.B., E.B., G.N.F., J.N.), Malmö University Hospital, Lund University; and Department of Biomedical Laboratory Science (G.N.F.), Malmö University, Sweden.

Correspondence to Maria Wigren, Department of Clinical Sciences, Entrance 72;91:12, Malmö University Hospital, 20502 Malmö, Sweden. E-mail maria.wigren{at}med.lu.se

The immune system represents a promising novel target for prevention of atherosclerosis. Several pilot vaccines that reduce atherosclerosis in experimental animals have been developed. The aluminum hydroxide adjuvant Alum has been shown to have antiatherogenic properties in itself, suggesting that it may be a suitable adjuvant in possible future atherosclerosis vaccines. To characterize the immune pathways mediating this protection, we treated wild-type C57BL/6 and Apoe^–/– mice with Alum or PBS. Analyses of splenocytes isolated from 12-week-old mice demonstrated that Alum increased the presence of CD4⁺CD25⁺FoxP3⁺ regulatory T cells and downregulated the expression of T cell activation markers CD28 and ICOS in Apoe^–/– mice but not in C57BL/6 wild-type mice. A similar immunosuppressive phenotype was found also in 25-week-old Apoe^–/– mice and was associated with reduced atherosclerosis. Alum precipitates recovered from the injection site of Apoe^–/– mice contained antigens derived from oxidized LDL. These findings demonstrate that treatment of Apoe^–/– mice with Alum results in an increase of regulatory T cells and suggest that these are activated by tolerogenic antigen-presenting cells presenting oxidized LDL antigens. Our findings provide improved mechanistic understanding of the atheroprotective properties of aluminum hydroxide adjuvants but also point to the importance of determining if hypercholesterolemia may compromise the efficacy of Alum-containing vaccines used clinically today.

Key Words: atherosclerosis • lipids • regulatory T cells • vaccine