Vaccination strategies in atherosclerosis

Summary

The treatment of atherosclerosis is currently based on lipid lowering in combination with anti-inflammatory therapies that slow the progression of atherosclerosis. Still, we are not able to fully inhibit the formation or progression of atherosclerotic lesions. A very effective strategy in other disease pathologies is vaccination, in which the body is challenged with the culprit protein or micro-organism in order to create a highly specific humoral immune-response. Immunisation can typically be divided into active or passive immunisation. Active immunisation occurs naturally when the body is exposed to certain microbes or antigens, but also artificially in the case of vaccination. Exposure to a microbe or antigen will result in the production of (antigen specific) antibodies. Passive immunisation is defined as the transfer of humoral immunity (as a result of antibody transfer). Another mechanism to ensure immune-protection is tolerance induction. Immune tolerance occurs naturally to prevent immune responses to ‘self-antigens’, but can also be induced to non-self antigens. Acquired tolerance to foreign antigens is accompanied by suppression of cellular and/or humoral immune response to the introduced antigen. In its most effective way, vaccination can result in a lifelong protection against the targeted pathology, and therefore the development of an atherosclerosis-specific vaccination is of high importance in the future prevention of atherosclerosis. One of the difficulties in developing effective vaccination strategies for atherosclerosis is the selection of a specific antigen to target. So far vaccination strategies have been based on targeting of lipidantigens, inflammation-derived antigens, and recently cell-based vaccination strategies have been employed; but also the cardiovascular ‘side-effects’ of infection-based vaccines are worthy of our attention. This review describes the current status-quo on classical antibody associated vaccination strategies but also includes promising immunemodulation approaches that may lead to a clinical application.

Keywords

Atherosclerosis - vaccination - immunology

• References

• 1 Meier CR, Jick SS, Derby LE. et al. Acute respiratory-tract infections and risk of first-time acute myocardial infarction. Lancet 1998; 351: 1467-1471.
• 2 Spodick DH, Flessas AP, Johnson MM. Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched control patients. Am J Cardiol 1984; 53: 481-482.
• 3 Bainton D, Jones GR, Hole D. Influenza and ischaemic heart disease--a possible trigger for acute myocardial infarction?. Int J Epidemiol 1978; 7: 231-239.
• 4 Cold exposure and winter mortality from ischaemic heart disease, cerebrovascular disease, respiratory disease, and all causes in warm and cold regions of Europe. The Eurowinter Group. Lancet 1997; 349: 1341-1346.
• 5 Reichert TA, Simonsen L, Sharma A. et al. Influenza and the winter increase in mortality in the United States, 1959-1999. Am J Epidemiol 2004; 160: 492-502.
• 6 Haidari M, Wyde PR, Litovsky S. et al. Influenza virus directly infects, inflames, and resides in the arteries of atherosclerotic and normal mice. Atherosclerosis 2010; 208: 90-96.
• 7 Gurfinkel EP, de la Fuente RL, Mendiz O. et al. Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: the FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study. Circulation 2002; 105: 2143-2147.
• 8 Gurfinkel EP, Leon de la Fuente R, Mendiz O. et al. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study. Eur Heart J 2004; 25: 25-31.
• 9 Gurfinkel EP, de la Fuente RL. Two-year follow-up of the FLU Vaccination Acute Coronary Syndromes (FLUVACS) Registry. Tex Heart Inst J 2004; 31: 28-32.
• 10 Phrommintikul A, Kuanprasert S, Wongcharoen W. et al. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. Eur Heart J 2011; 32: 1730-1735.
• 11 Zhu T, Carcaillon L, Martinez I. et al. Association of influenza vaccination with reduced risk of venous thromboembolism. Thromb Haemost 2009; 102: 1259-1264.
• 12 Binder CJ, Horkko S, Dewan A. et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003; 9: 736-743.
• 13 Lamontagne F, Garant MP, Carvalho JC. et al. Pneumococcal vaccination and risk of myocardial infarction. CMAJ 2008; 179: 773-777.
• 14 Nguyen JT, Myers N, Palaia J. et al. Humoral responses to oxidized low-density lipoprotein and related bacterial antigens after pneumococcal vaccine. Transl Res 2007; 150: 172-179.
• 15 Damoiseaux J, Rijkers G, Tervaert JW. Pneumococcal vaccination does not increase circulating levels of IgM antibodies to oxidized LDL in humans and therefore precludes an anti-atherogenic effect. Atherosclerosis 2007; 190: 10-11.
• 16 Barter PJ, Caulfield M, Eriksson M. et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109-2122.
• 17 Rittershaus CW, Miller DP, Thomas LJ. et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20: 2106-2112.
• 18 Gaofu Q, Jun L, Xin Y. et al. Vaccinating rabbits with a cholesteryl ester transfer protein (CETP) B-Cell epitope carried by heat shock protein-65 (HSP65) for inducing anti-CETP antibodies and reducing aortic lesions in vivo. J Cardiovasc Pharmacol 2005; 45: 591-598.
• 19 Mao D, Kai G, Gaofu Q. et al. Intramuscular immunization with a DNA vaccine encoding a 26-amino acid CETP epitope displayed by HBc protein and containing CpG DNA inhibits atherosclerosis in a rabbit model of atherosclerosis. Vaccine 2006; 24: 4942-4950.
• 20 Yuan X, Yang X, Cai D. et al. Intranasal immunization with chitosan/pCETP nanoparticles inhibits atherosclerosis in a rabbit model of atherosclerosis. Vaccine 2008; 26: 3727-3734.
• 21 Qi G, Li J, Wang S. et al. A chimeric peptide of intestinal trefoil factor containing cholesteryl ester transfer protein B cell epitope significantly inhibits atherosclerosis in rabbits after oral administration. Peptides 2011; 32: 790-796.
• 22 Witztum JL, Steinbrecher UP, Fisher M. et al. Nonenzymatic glucosylation of homologous low density lipoprotein and albumin renders them immunogenic in the guinea pig. Proc Natl Acad Sci USA 1983; 80: 2757-2761.
• 23 Palinski W, Rosenfeld ME, Yla-Herttuala S. et al. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci USA 1989; 86: 1372-1376.
• 24 Palinski W, Ord VA, Plump AS. et al. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb 1994; 14: 605-616.
• 25 Rosenfeld ME, Palinski W, Yla-Herttuala S. et al. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis 1990; 10: 336-349.
• 26 Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA 1995; 92: 821-825.
• 27 Ameli S, Hultgardh-Nilsson A, Regnstrom J. et al. Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol 1996; 16: 1074-1079.
• 28 Freigang S, Horkko S, Miller E. et al. Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vasc Biol 1998; 18: 1972-1982.
• 29 Zhou X, Caligiuri G, Hamsten A. et al. LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 108-114.
• 30 Fredrikson GN, Hedblad B, Berglund G. et al. Identification of immune responses against aldehyde-modified peptide sequences in apoB associated with cardiovascular disease. Arterioscler Thromb Vasc Biol 2003; 23: 872-878.
• 31 Fredrikson GN, Soderberg I, Lindholm M. et al. Inhibition of atherosclerosis in apoE-null mice by immunization with apoB-100 peptide sequences. Arterioscler Thromb Vasc Biol 2003; 23: 879-884.
• 32 Fredrikson GN, Bjorkbacka H, Soderberg I. et al. Treatment with apo B peptide vaccines inhibits atherosclerosis in human apo B-100 transgenic mice without inducing an increase in peptide-specific antibodies. J Intern Med 2008; 264: 563-570.
• 33 Wigren M, Kolbus D, Duner P. et al. Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 2011; 269: 546-556.
• 34 Schiopu A, Frendeus B, Jansson B. et al. Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice. J Am Coll Cardiol 2007; 50: 2313-2318.
• 35 Goncalves I, Nitulescu M, Ares MP. et al. Identification of the target for therapeutic recombinant anti-apoB-100 peptide antibodies in human atherosclerotic lesions. Atherosclerosis 2009; 205: 96-100.
• 36 De Maio A. Heat shock proteins: facts, thoughts, and dreams. Shock 1999; 11: 1-12.
• 37 Antonova G, Lichtenbeld H, Xia T. et al. Functional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc 2007; 37: 19-35.
• 38 Nishikawa M, Takemoto S, Takakura Y. Heat shock protein derivatives for delivery of antigens to antigen presenting cells. Int J Pharm 2008; 354: 23-27.
• 39 Hochleitner BW, Hochleitner EO, Obrist P. et al. Fluid shear stress induces heat shock protein 60 expression in endothelial cells in vitro and in vivo. Arterioscler Thromb Vasc Biol 2000; 20: 617-623.
• 40 Frostegard J, Kjellman B, Gidlund M. et al. Induction of heat shock protein in monocytic cells by oxidized low density lipoprotein. Atherosclerosis 1996; 121: 93-103.
• 41 Oehler R, Schmierer B, Zellner M. et al. Endothelial cells downregulate expression of the 70 kDa heat shock protein during hypoxia. Biochem Biophys Res Commun 2000; 274: 542-547.
• 42 Afek A, George J, Gilburd B. et al. Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis. J Autoimmun 2000; 14: 115-121.
• 43 Maron R, Sukhova G, Faria AM. et al. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 2002; 106: 1708-1715.
• 44 van Puijvelde GH, van Es T, van Wanrooij EJ. et al. Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27: 2677-2683.
• 45 Alexander J, Sidney J, Southwood S. et al. Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1994; 1: 751-761.
• 46 Hauer AD, Uyttenhove C, de Vos P. et al. Blockade of interleukin-12 function by protein vaccination attenuates atherosclerosis. Circulation 2005; 112: 1054-1062.
• 47 Liu K, Catalfamo M, Li Y. et al. IL-15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells. Proc Natl Acad Sci USA 2002; 99: 6192-6197.
• 48 Allavena P, Giardina G, Bianchi G. et al. IL-15 is chemotactic for natural killer cells and stimulates their adhesion to vascular endothelium. J Leukoc Biol 1997; 61: 729-735.
• 49 Alleva DG, Kaser SB, Monroy MA. et al. IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition. J Immunol 1997; 159: 2941-2951.
• 50 van Es T, van Puijvelde GH, Michon IN. et al. IL-15 aggravates atherosclerotic lesion development in LDL receptor deficient mice. Vaccine 2011; 29: 976-983.
• 51 Hauer AD, van Puijvelde GH, Peterse N. et al. Vaccination against VEGFR2 attenuates initiation and progression of atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27: 2050-2057.
• 52 Petrovan RJ, Kaplan CD, Reisfeld RA. et al. DNA vaccination against VEGF receptor 2 reduces atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2007; 27: 1095-1100.
• 53 van Wanrooij EJ, de Vos P, Bixel MG. et al. Vaccination against CD99 inhibits atherogenesis in low-density lipoprotein receptor-deficient mice. Cardiovasc Res 2008; 78: 590-596.
• 54 Hauer AD, Habets KL, van Wanrooij EJ. et al. Vaccination against TIE2 reduces atherosclerosis. Atherosclerosis 2009; 204: 365-371.
• 55 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J Am Med Assoc 2002; 287: 356-359.
• 56 Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908-913.
• 57 Wren AM, Small CJ, Ward HL. et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000; 141: 4325-4328.
• 58 Dezaki K, Sone H, Yada T. Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis. Pharmacol Ther 2008; 118: 239-249.
• 59 Garcia EA, Korbonits M. Ghrelin and cardiovascular health. Curr Opin Pharmacol 2006; 6: 142-147.
• 60 Kleinz MJ, Maguire JJ, Skepper JN. et al. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res 2006; 69: 227-235.
• 61 Wiley KE, Davenport AP. Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol 2002; 136: 1146-1152.
• 62 Kellokoski E, Kummu O, Serpi R. et al. Ghrelin vaccination decreases plasma MCP-1 level in LDLR(-/-)-mice. Peptides 2009; 30: 2292-2300.
• 63 Bourinbaiar AS, Jirathitikal V. Effect of oral immunization with pooled antigens derived from adipose tissue on atherosclerosis and obesity indices. Vaccine 2010; 28: 2763-2768.
• 64 Fredrikson GN, Anand DV, Hopkins D. et al. Associations between autoantibodies against apolipoprotein B-100 peptides and vascular complications in patients with type 2 diabetes. Diabetologia 2009; 52: 1426-1433.
• 65 Figdor CG, de Vries IJ, Lesterhuis WJ. et al. Dendritic cell immunotherapy: mapping the way. Nat Med 2004; 10: 475-480.
• 66 Dubsky P, Ueno H, Piqueras B. et al. Human dendritic cell subsets for vaccination. J Clin Immunol 2005; 25: 551-572.
• 67 Habets KL, van Puijvelde GH, van Duivenvoorde LM. et al. Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice. Cardiovasc Res 2010; 85: 622-630.
• 68 Bellinghausen I, Brand U, Steinbrink K. et al. Inhibition of human allergic T-cell responses by IL-10-treated dendritic cells: differences from hydrocortisone-treated dendritic cells. J Allergy Clin Immunol 2001; 108: 242-249.
• 69 Lan YY, Wang Z, Raimondi G. et al. „Alternatively activated“ dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig. J Immunol 2006; 177: 5868-5877.
• 70 Steinbrink K, Wolfl M, Jonuleit H. et al. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 1997; 159: 4772-4780.
• 71 Wakkach A, Fournier N, Brun V. et al. Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 2003; 18: 605-617.
• 72 Hermansson A, Johansson DK, Ketelhuth DF. et al. Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation 2011; 123: 1083-1091.
• 73 van Es T, van Puijvelde GH, Foks AC. et al. Vaccination against Foxp3(+) regulatory T cells aggravates atherosclerosis. Atherosclerosis 2010; 209: 74-80.
• 74 Khallou-Laschet J, Tupin E, Caligiuri G. et al. Atheroprotective effect of adjuvants in apolipoprotein E knockout mice. Atherosclerosis 2006; 184: 330-341.
• 75 Wigren M, Bengtsson D, Duner P. et al. Atheroprotective effects of Alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells. Circ Res 2009; 104: e62-70.