Treatment with apo B peptide vaccines inhibits atherosclerosis in human apo B‐100 transgenic mice without inducing an increase in peptide‐specific antibodies

Fredrikson, Gunilla Nordin; Björkbacka, Harry; Söderberg, Ingrid; Ljungcrantz, Irena; Nilsson, Jan

doi:10.1111/j.1365-2796.2008.01995.x

Cited by 86 publications

(60 citation statements)

References 35 publications

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“…A parallel group of wild-type C57BL/6 wild-type mice received the same type of treatment to determine the possible influence of hypercholesterolemia on Alum-induced immune responses. The cholesterol and triglyceride levels were 17 Figure 1A). There was also a decreased expression of the T-cell activation markers ICOS and CD28 on CD4 cells from Apoe Ϫ/Ϫ mice treated with Alum ( Figure 1B and 1C).…”

Section: Resultsmentioning

confidence: 99%

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

Wigren

Bengtsson

Dunér

et al. 2009

Circulation Research

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Abstract-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. Key Words: atherosclerosis Ⅲ lipids Ⅲ regulatory T cells Ⅲ vaccine T he possibility of treating autoimmune diseases by immune modulation with autoantigens has been gaining increasing attention. Ongoing clinical trials in this area include vaccines for type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease. 1 A vaccine against atherosclerosis based on modulation of autoimmune responses against antigens in oxidized LDL is also in late preclinical development. 2 Adjuvants enhancing the immunogenicity of vaccine antigens are critical components of almost all vaccines and play an important role in modulating the characteristics of the subsequent immune response. Aluminumcontaining adjuvants are the most widely used adjuvants in clinical vaccines, and their safety is well documented. 3 Interestingly, it has recently been demonstrated that the aluminum hydroxide adjuvant Alum has atheroprotective properties in itself, suggesting that it could be a particularly suitable adjuvant in a potential future atherosclerosis vaccine. 4 Aluminum-containing adjuvants primarily induce humoral immunity but are less effective in activating T cellmediated delayed-type hypersensitivity immune responses. 5 Their mechanism of action is generally considered to involve delayed clearance of the antigen from the injection site, 6 induction of a local inflammatory response stimulating the recruitment and activation of antigen-presenting cells (APCs), 7-10 and conversion of soluble antigens into a particulate form facilitating their uptake by phagocytosis in APCs. 11,12 However, it is unclear how these mechanisms can contribute to a protection against atherosclerosis when Alum is administered in absence of an antigen. In the present study, we investigated the possibility that Alum, when injected into a hypercholesterolemic environment, could adsorb self antigens and activate immune responses against these in a manner that contributes to protection against atherosclerosis. Materials and Methods Mice, Immunization, and Tissue PreparationMale apolipoprotein (apo)E-deficient and wild-type C57BL/6 mice were from Taconic Laboratory. Food and tap water were administered ad libitum. Mice were given subcutaneous injections (100 L) with Alum (aluminum hydroxide; Pierce) in PBS (1:1) at 6, 9, and 11 weeks of age. Injections of only PBS served as controls. Mice were euthanized at 12 or 25 weeks of age by intraperitoneal injection of ketamine and xylazine. Spleens were harvested and stored in PBS on Original

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Section: Resultsmentioning

confidence: 99%

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

Wigren

Bengtsson

Dunér

et al. 2009

Circulation Research

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“…Blots were washed in TBS-T and absent, as is the case in homozygous familial hypercholesterolemia (hoFH). While efforts are currently underway to evaluate an apoB-specifi c peptide vaccine in animal models, this approach has not been demonstrated to be safe or effi cacious in nonhuman primates or man ( 9,10 ).…”

Section: Immunoblottingmentioning

confidence: 99%

Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice

Mullick

Graham

et al. 2011

Journal of Lipid Research

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) mice. ISIS 147764 was administered weekly at 25-100 mg/kg for 10-12 weeks and produced dose-dependent reductions of hepatic apoB mRNA and plasma LDL by 60-90%. No effects on these parameters were seen in mice receiving control ASOs. ApoB ASO treatment also produced dose-dependent reductions of aortic en face and sinus atherosclerosis from 50-90%, with high-dose treatment displaying less disease than the saline-treated, chow-fed LDLr

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“…Immunization of apo E-deficient mice with some of these apo B-100 peptides induces an Ig switch from IgM to IgG that is accompanied by an inhibition of atherosclerosis (13)(14)(15). To study the possible atheoprotective effects of this IgG, we produced human IgG1 specific for an apo B-100 peptide.…”

mentioning

confidence: 99%

FcγRIIB Inhibits the Development of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Zhao

Wigren

Dunér

et al. 2010

The Journal of Immunology

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The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcγR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcγRIIB in atherosclerosis has not been defined. Bone marrow cells from FcγRIIB-deficient mice and C57BL/6 control mice were transplanted to low-density lipoprotein receptor-deficient mice. Atherosclerosis was induced by feeding the recipient mice a high-fat diet for 8 wk and evaluated using Oil Red O staining of the descending aorta at sacrifice. The molecular mechanisms triggering atherosclerosis was studied by examining splenic B and T cells, as well as Th1 and Th2 immune responses using flow cytometry and ELISA. The atherosclerotic lesion area in the descending aorta was ~5-fold larger in mice lacking FcγRIIB than in control mice (2.75 ± 2.57 versus 0.44 ± 0.42%; p < 0.01). Moreover, the FcγRIIB deficiency resulted in an amplified splenocyte proliferative response to Con A stimulation (proliferation index 30.26 ± 8.81 versus 2.96 ± 0.81%, p < 0.0001) and an enhanced expression of MHC class II on the B cells (6.65 ± 0.64 versus 2.33 ± 0.25%; p < 0.001). In accordance, an enlarged amount of CD25-positive CD4 T cells was found in the spleen (42.74 ± 4.05 versus 2.45 ± 0.31%; p < 0.0001). The plasma Ab and cytokine pattern suggested increased Th1 and Th2 immune responses, respectively. These results show that FcγRIIB inhibits the development of atherosclerosis in mice. In addition, they indicate that absence of the inhibiting IgG receptor cause disease, depending on an imbalance of activating and inhibiting immune cells.

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Treatment with apo B peptide vaccines inhibits atherosclerosis in human apo B‐100 transgenic mice without inducing an increase in peptide‐specific antibodies

Cited by 86 publications

References 35 publications

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

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

Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice

FcγRIIB Inhibits the Development of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

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