CD8+ T Cells Mediate the Athero-Protective Effect of Immunization with an ApoB-100 Peptide

Abstract

Immunization of hypercholesterolemic mice with selected apoB-100 peptide antigens reduces atherosclerosis but the precise immune mediators of athero-protection remain unclear. In this study we show that immunization of apoE (-/-) mice with p210, a 20 amino acid apoB-100 related peptide, reduced aortic atherosclerosis compared with PBS or adjuvant/carrier controls. Immunization with p210 activated CD8+ T cells, reduced dendritic cells (DC) at the site of immunization and within the plaque with an associated reduction in plaque macrophage immunoreactivity. Adoptive transfer of CD8+ T cells from p210 immunized mice recapitulated the athero-protective effect of p210 immunization in naïve, non-immunized mice. CD8+ T cells from p210 immunized mice developed a preferentially higher cytolytic response against p210-loaded dendritic cells in vitro. Although p210 immunization profoundly modulated DCs and cellular immune responses, it did not alter the efficacy of subsequent T cell dependent or independent immune response to other irrelevant antigens. Our data define, for the first time, a role for CD8+ T cells in mediating the athero-protective effects of apoB-100 related peptide immunization in apoE (-/-) mice.

Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis – A review of the experimental evidence

“…Activation of CD8 + T cells has also been associated with increased plaque formation in these mice (34). In apparent contrast with these observations, atherosclerosis protection achieved by immunization with apolipoprotein B (apoB) peptide has been suggested to involve CD8 + T cells (35). On the other hand, Tap1 …”

Vaccine against arteriosclerosis: an update

“…This is based on the observations that (1) apoB-100 peptide immunization reduced atherosclerosis without an increase in peptide-specific immunoglobulin (Ig)G, 19 and the induced antibody titers did not correlate with the lesion size; 20 (2) Adoptive transfer of B-cells from p210-immunized mice to nonimmunized recipient mice did not confer atheroprotective effect. 18 However, immunization with p210 peptide did alter the natural history of p210 antibody levels in apoE -/-mice. In control mice, p210 IgG titer remained low between baseline and 25 weeks; whereas mice receiving adjuvant only or p210 vaccine developed high p210 IgG titer at 25 weeks.…”

“…Interestingly IgG titer at 25 weeks from p210-immunized mice was lower when compared with that of mice receiving adjuvant only. 18 p210 IgM has a different profile; low level before immunization but titers increased over time, regardless of whether or not mice were immunized with p210 vaccine. This observation suggests that: (1) an endogenous IgM immune response against p210 exists, (2) induction of p210 IgG may serve as a marker of vaccination effect but not a marker of atheroprotective efficacy of the p210 vaccine.…”

“…16,17 Knowing the defined epitope makes more definitive immunologic studies possible; our teams have been using p210 as a prototype antigen in vaccine formulations due to its consistent atheroprotective effects. [18][19][20] Mechanisms of action of p210 vaccine Immunization with the p210 vaccine resulted in a significant reduction of aortic atherosclerosis compared with controls in murine model of atherosclerosis. 18 Given that immunization activates both B and T-cells, 18 it is important to delineate the subset(s) of lymphocytes which mediate the p210 vaccine's atheroprotective effect.…”

“…[18][19][20] Mechanisms of action of p210 vaccine Immunization with the p210 vaccine resulted in a significant reduction of aortic atherosclerosis compared with controls in murine model of atherosclerosis. 18 Given that immunization activates both B and T-cells, 18 it is important to delineate the subset(s) of lymphocytes which mediate the p210 vaccine's atheroprotective effect. Currently existing experimental evidence does not support a strong role for the humoral response in mediating the protective effect of active immunization using the p210 vaccine.…”