Immune-modulation by polyclonal IgM treatment reduces atherosclerosis in hypercholesterolemic apoE−/− mice

AbstractObjectiveGamma-globulin treatment reduces experimental atherosclerosis by modulating immune function; however the effect of IgM on atherosclerosis is not known. We investigated the effect of serum-derived, non-immune polyclonal IgM (Poly-IgM) on atherosclerosis in mice with advanced disease and also assessed its immune-modulatory effects.Methods and resultsAortic atherosclerosis was assessed in apoE−/− mice fed atherogenic diet starting at 6 weeks of age. In addition, mice were also subjected to perivascular cuff injury to the carotid artery at 25 weeks of age to induce accelerated atherosclerosis. At the time of injury, the mice were treated weekly with a commercially available Poly-IgM (0.4mg/mouse) or PBS for 4 weeks and euthanized at 29 weeks of age. Poly-IgM reduced aortic atherosclerosis, and reduced lesion size in the aortic sinus and injured carotid artery, without significant changes in serum cholesterol levels. Poly-IgM treatment was associated with increased anti-oxLDL IgG titers and a reduction in the % splenic CD4+ T cells compared to controls. The splenic CD4+ T cell cultured from the Poly-IgM treated mice had reduced proliferation in vitro compared with controls.ConclusionPoly-IgM treatment reduced aortic and accelerated carotid atherosclerosis in apoE−/− mice in association with increased anti-oxLDL IgG titers, and reduced number and proliferative function of splenic CD4+ T cells. Our study identifies a novel athero-protective and immunomodulatory role for non-immune polyclonal IgM

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

BackgroundLL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients.Methods and resultsThe activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls. Specifically, CD8+CD69+CD137+ T cells were significantly increased by LL-37 stimulation in ACS PBMCs. T effector cell response to LL-37 were either HLA dependent or independent as determined by blocking with monoclonal antibody to either Class-I HLA or Class-II HLA. Blocking of immune checkpoints PD-1 and CTLA-4 demonstrated the control of self-reactive T cell response to LL-37 was modulated predominantly by CTLA-4. Platelets from healthy controls down-modulated CD8+CD69+CD137+ T cell response to LL-37 in autologous PBMCs. CD8+CD69+CD137+ T cell AIM profile negatively correlated with platelet count in ACS patients.ConclusionsOur report demonstrates that the immune response to the autoantigen LL-37 in ACS patients is characterized specifically by CD8+CD69+CD137+ T cell AIM profile with persistent T cell activation and the generation of immunologic memory. The results provide potentially novel insight into mechanistic pathways of antigen-specific immune signaling in ACS

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

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

Enhanced Neointima Formation Following Arterial Injury in Immune Deficient Rag-1−/− Mice Is Attenuated by Adoptive Transfer of CD8+ T cells

T cells modulate neointima formation after arterial injury but the specific T cell population that is activated in response to arterial injury remains unknown. The objective of the study was to identify the T cell populations that are activated and modulate neointimal thickening after arterial injury in mice. Arterial injury in wild type C57Bl6 mice resulted in T cell activation characterized by increased CD4+CD44hi and CD8+CD44hi T cells in the lymph nodes and spleens. Splenic CD8+CD25+ T cells and CD8+CD28+ T cells, but not CD4+CD25+ and CD4+CD28+ T cells, were also significantly increased. Adoptive cell transfer of CD4+ or CD8+ T cells from donor CD8−/− or CD4−/− mice, respectively, to immune-deficient Rag-1−/− mice was performed to determine the T cell subtype that inhibits neointima formation after arterial injury. Rag-1−/− mice that received CD8+ T cells had significantly reduced neointima formation compared with Rag-1−/− mice without cell transfer. CD4+ T cell transfer did not reduce neointima formation. CD8+ T cells from CD4−/− mice had cytotoxic activity against syngeneic smooth muscle cells in vitro. The study shows that although both CD8+ T cells and CD4+ T cells are activated in response to arterial injury, adoptive cell transfer identifies CD8+ T cells as the specific and selective cell type involved in inhibiting neointima formation

Active and passive immunization for atherosclerosis

This review summarizes experimental findings that highlight the role of immune mechanisms in atherosclerosis and the potential atheroprotective effects of active or passive immunization strategies. Immunomodulation therapy appears to be feasible and effective, suggesting that a vaccine for atherosclerosis can be developed for clinical testing. Given the increasing number of patients with atherosclerotic disease on current therapy, a new therapy is needed and an immunization strategy could provide such a possibility. Several questions regarding this approach remain unanswered, however, such as choice of optimal antigens, choice of most effective adjuvants, the optimal route of administration, durability of effects and safety, but cautious optimism remains that a vaccine-based approach has the potential to become a part of the armamentarium for atherosclerotic vascular disease

Vaccine for Atherosclerosis.

Atherosclerosis is an immune-mediated inflammatory disease of the arterial wall, with both the innate and adaptive immune systems responding to many endogenous and exogenous antigens. Both proatherogenic as well as atheroprotective roles have been identified for the immune system in atherosclerosis. Hence, it is conceivable that an immunomodulatory strategy via active immunization against many of these antigens could potentially alter the natural history of atherosclerosis. This review discusses: 1) the complex role of important components of the innate and adaptive immune systems in atherogenesis; 2) the nature of many antigens that have been tested successfully in vaccine formulations to reduce atherosclerosis in pre-clinical experimental models; and 3) the potential opportunities and challenges for clinical application of vaccination for atherosclerosis in the future