Atheroprotective effects of Alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells.
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.
Wigren
Maria
M
Department of Clinical Sciences, Entrance 72;91:12, Malmö University Hospital, 20502 Malmö, Sweden. maria.wigren@med.lu.se
Bengtsson
Daniel
D
Dunér
Pontus
P
Olofsson
Katarina
K
Björkbacka
Harry
H
Bengtsson
Eva
E
Fredrikson
Gunilla Nordin
GN
Nilsson
Jan
J
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000534:Alum Compounds / Q000494:pharmacology*; D000536:Aluminum Hydroxide / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D006937:Hypercholesterolemia / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects*; D060889:Inducible T-Cell Co-Stimulator Protein; D008077:Lipoproteins, LDL / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014612:Vaccines / Q000276:immunology / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000945:Antigens, Differentiation, T-Lymphocyte; D001057:Apolipoproteins E; D018106:CD28 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D008077:Lipoproteins, LDL; D014612:Vaccines; C099252:oxidized low density lipoprotein; C041524:aluminum sulfate; D000536:Aluminum Hydroxide