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.
Highlights
Adaptive and innate immunity have been implicated in atherogenesis and pre-clinical studies have suggested that immuno-modulating therapies can reduce atherosclerosis [1,2]
Recent reports show that different immunization strategies using the same peptide antigen yield different immune responses, yet still provide protection against atherosclerosis [6,7]
We showed that: (a) subcutaneous p210 immunization elicited a functional CD8+ T cell immune response; (b) p210 immunization reduces dendritic cells (DC) at the immunization sites and in atherosclerotic plaques; (c) the athero-protective effect of subcutaneous p210 immunization is mediated by CD8+ T cells but not by CD4+CD25+ T cells or B cells; and (d) DCs are potential targets of cytolytic CD8+ T cells elicited by p210 immunization
Summary
Adaptive and innate immunity have been implicated in atherogenesis and pre-clinical studies have suggested that immuno-modulating therapies can reduce atherosclerosis [1,2] One such strategy involves active immunization using apoB-100 related peptide antigens [3,4]. Intranasal immunization of apoE(-/-) mice with a p210-CTB fusion protein preparation reduced atherosclerosis by 35% with increased IgG titers against p210 and CD4+ T regulatory cells without further elucidation of the role of either immune response [7]. Both studies concluded that the protection against atherosclerosis was independent of p210 antibody response. We designed a series of experiments to characterize the immune response to p210 immunization and to define the type of immune cells that mediate the athero-protective effect of p210 immunization
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