ApoB-100-Related Peptide Vaccine and Aortic Aneurysm Formation
ApoB-100-Related Peptide Vaccine and Aortic Aneurysm Formation
Background T cells and macrophages are implicated in the pathogenesis of aortic aneurysm (AA) and atherosclerosis. We recently demonstrated that a vaccine using an apoB-100–related peptide p210 reduces atherosclerosis with favorable modulation of CD8 T cells in apolipoprotein E–deficient (apoE) mice.
Objectives This study hypothesized that a p210 vaccine could reduce AA formation in the angiotensin II (Ang II)–induced AA model.
Methods Male apoE mice were immunized with p210 vaccine and implanted with an Ang II–releasing pump for 4 weeks. Flow cytometry assessed T cell activation and phenotype. Interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) expression were assessed using reverse transcription polymerase chain reaction. We used ex vivo aortic explants to test monocyte adhesion and in vitro cocultures to evaluate CD8 T cell function.
Results The p210 vaccine activated CD8 T cells and reduced AA formation and mortality due to AA rupture, which was attenuated by CD8 T cell depletion. Vaccination decreased expression of IL-6 and MCP-1 and reduced macrophage infiltration in the aorta. Cytotoxic T-lymphocyte assay showed that CD8 T cells from p210-immunized mice had higher lytic activity against Ang II–stimulated macrophages. The p210 vaccine decreased splenic Th17 cells, and in vitro coculture of CD4 and CD8 T cells showed that CD8 T cells from p210-immunized mice inhibited the polarization of CD4 T cells into Th17 cells. IL-17A mice infused with a higher dose of Ang II did not develop AA rupture.
Conclusions A p210 vaccine protected against Ang II–induced AA formation and mortality by reducing macrophage infiltration in the aorta and decreasing Th17 cell polarization. Our findings provide a potentially novel immunomodulating approach against AA.
Aortic aneurysm (AA) formation and its related complications account for more than 17,000 deaths/year in the United States, with multiple risk factors including older age, male sex, tobacco smoking, family history, hypertension, and atherosclerosis. Evidence supports the involvement of both innate and adaptive immune responses in vascular inflammation and the formation of atherosclerotic plaques. Immuno-inflammatory mechanisms also participate in forming AAs, as evidenced by the presence of immune cells, such as T cells and macrophages, and inflammatory cytokines (1–5). Macrophages, in particular, play a pivotal role in angiotensin II (Ang II)–induced AA formation and rupture. The interaction of T cells with antigen-presenting cells, such as macrophages and dendritic cells, thus provide the prime condition for immune activation. Clonal expansion of T cells in human AA strongly suggests antigenspecific immune activation, supporting the view that T cells are an important component of this complex disease.
We have demonstrated that immunization with an apolipoprotein B-100 (apoB-100)–related peptide, p210, reduces atherosclerosis in hyperlipidemic apolipoprotein E–deficient (apoE) mice. The antiatherosclerotic effect of p210 vaccine was due to immunomodulation of CD8 T cells independent of antibody production. Given the commonality of the inflammatory pathways and the involvement of T cells, modulation of T cell function also may be a potential strategy to temper AA formation. Hence, we tested the hypothesis that immunization with p210 vaccine could reduce aortic inflammation and AA formation in a murine model of AA induced by Ang II infusion.
Abstract and Introduction
Abstract
Background T cells and macrophages are implicated in the pathogenesis of aortic aneurysm (AA) and atherosclerosis. We recently demonstrated that a vaccine using an apoB-100–related peptide p210 reduces atherosclerosis with favorable modulation of CD8 T cells in apolipoprotein E–deficient (apoE) mice.
Objectives This study hypothesized that a p210 vaccine could reduce AA formation in the angiotensin II (Ang II)–induced AA model.
Methods Male apoE mice were immunized with p210 vaccine and implanted with an Ang II–releasing pump for 4 weeks. Flow cytometry assessed T cell activation and phenotype. Interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) expression were assessed using reverse transcription polymerase chain reaction. We used ex vivo aortic explants to test monocyte adhesion and in vitro cocultures to evaluate CD8 T cell function.
Results The p210 vaccine activated CD8 T cells and reduced AA formation and mortality due to AA rupture, which was attenuated by CD8 T cell depletion. Vaccination decreased expression of IL-6 and MCP-1 and reduced macrophage infiltration in the aorta. Cytotoxic T-lymphocyte assay showed that CD8 T cells from p210-immunized mice had higher lytic activity against Ang II–stimulated macrophages. The p210 vaccine decreased splenic Th17 cells, and in vitro coculture of CD4 and CD8 T cells showed that CD8 T cells from p210-immunized mice inhibited the polarization of CD4 T cells into Th17 cells. IL-17A mice infused with a higher dose of Ang II did not develop AA rupture.
Conclusions A p210 vaccine protected against Ang II–induced AA formation and mortality by reducing macrophage infiltration in the aorta and decreasing Th17 cell polarization. Our findings provide a potentially novel immunomodulating approach against AA.
Introduction
Aortic aneurysm (AA) formation and its related complications account for more than 17,000 deaths/year in the United States, with multiple risk factors including older age, male sex, tobacco smoking, family history, hypertension, and atherosclerosis. Evidence supports the involvement of both innate and adaptive immune responses in vascular inflammation and the formation of atherosclerotic plaques. Immuno-inflammatory mechanisms also participate in forming AAs, as evidenced by the presence of immune cells, such as T cells and macrophages, and inflammatory cytokines (1–5). Macrophages, in particular, play a pivotal role in angiotensin II (Ang II)–induced AA formation and rupture. The interaction of T cells with antigen-presenting cells, such as macrophages and dendritic cells, thus provide the prime condition for immune activation. Clonal expansion of T cells in human AA strongly suggests antigenspecific immune activation, supporting the view that T cells are an important component of this complex disease.
We have demonstrated that immunization with an apolipoprotein B-100 (apoB-100)–related peptide, p210, reduces atherosclerosis in hyperlipidemic apolipoprotein E–deficient (apoE) mice. The antiatherosclerotic effect of p210 vaccine was due to immunomodulation of CD8 T cells independent of antibody production. Given the commonality of the inflammatory pathways and the involvement of T cells, modulation of T cell function also may be a potential strategy to temper AA formation. Hence, we tested the hypothesis that immunization with p210 vaccine could reduce aortic inflammation and AA formation in a murine model of AA induced by Ang II infusion.
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