Restoring Immune Tolerance in Atherosclerosis: Role of Regulatory Immune Response in Atheroprotection
DOI:
https://doi.org/10.14205/2310-6980.2014.02.02.2Keywords:
Atherosclerosis, Autoimmunity, Immune tolerance, Regulatory T cells.Abstract
Cardiovascular diseases remain the most significant cause of global mortality despite advances in medicine and new drug development. Atherosclerotic lesions start developing in childhood, progress over decades and manifest as coronary artery disease, stroke or peripheral arterial disease later in life. Chronic inflammation in the arterial wall mediated by altered immune response is vital during the development of atherosclerosis. Antigen specific immune therapy is an elegant approach to target disease related antigens. Immune tolerance to atherogenic self antigens has gained importance as an efficient therapy to control atherosclerosis in recent years. This review discusses the recent development and our understanding of immune tolerance in atherosclerosis and the role of regulatory immune response in protection against the disease.
References
Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6(7): 508-19. http://dx.doi.org/10.1038/nri1882
Hermansson A, Ketelhuth DF, Strodthoff D, Wurm M, Hansson EM, Nicoletti A, et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med. 2010 May 10; 207(5): 1081-93. http://dx.doi.org/10.1084/jem.20092243
Ketelhuth DF, Hansson GK. Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thromb Haemost. 2011 Nov; 106(5): 779-86. http://dx.doi.org/10.1160/TH11-05-0321
Lutgens E, Binder CJ. Immunology of atherosclerosis. Thromb Haemost. Nov; 106(5): 755-6.
Paoletti R, Gotto AM, Jr., Hajjar DP. Inflammation in atherosclerosis and implications for therapy. Circulation. 2004 Jun 15; 109(23 Suppl 1): III20-6.
Cuneo AA, Autieri MV. Expression and function of antiinflammatory interleukins: the other side of the vascular response to injury. Curr Vasc Pharmacol. 2009 Jul; 7(3): 267- 76. http://dx.doi.org/10.2174/157016109788340721
Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute Coronary Events. Circulation. 2012 March 6, 2012; 125(9): 1147-56.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005 Oct 8; 366(9493): 1267-78. http://dx.doi.org/10.1016/S0140-6736(05)67394-1
Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol. 2001 Dec; 21(12): 1876-90. http://dx.doi.org/10.1161/hq1201.100220
Binder CJ, Hartvigsen K, Witztum JL. Promise of immune modulation to inhibit atherogenesis. J Am Coll Cardiol. 2007 Aug 7; 50(6): 547-50. http://dx.doi.org/10.1016/j.jacc.2007.04.054
Nilsson J, Fredrikson GN, Bjorkbacka H, Chyu KY, Shah PK. Vaccines modulating lipoprotein autoimmunity as a possible future therapy for cardiovascular disease. J Intern Med. 2009 Sep; 266(3): 221-31. http://dx.doi.org/10.1111/j.1365-2796.2009.02150.x
Wick G, Jakic B, Buszko M, Wick MC, Grundtman C. The role of heat shock proteins in atherosclerosis. Nat Rev Cardiol. 2014 Sep; 11(9): 516-29. http://dx.doi.org/10.1038/nrcardio.2014.91
Matusik P, Guzik B, Weber C, Guzik TJ. Do we know enough about the immune pathogenesis of acute coronary syndromes to improve clinical practice? Thromb Haemost. 2012 Sep 4; 108(3): 443-56. http://dx.doi.org/10.1160/TH12-05-0341
Grundtman C, Kreutmayer SB, Almanzar G, Wick MC, Wick G. Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011 May; 31(5): 960-8. http://dx.doi.org/10.1161/ATVBAHA.110.217877
Hansson GK. Atherosclerosis--an immune disease: The Anitschkov Lecture 2007. Atherosclerosis. 2009 Jan; 202(1): 2-10. http://dx.doi.org/10.1016/j.atherosclerosis.2008.08.039
Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011 Mar; 12(3): 204-12. http://dx.doi.org/10.1038/ni.2001
Monaco C, Gregan SM, Navin TJ, Foxwell BM, Davies AH, Feldmann M. Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. Circulation. 2009 Dec 15; 120(24): 2462-9. http://dx.doi.org/10.1161/CIRCULATIONAHA.109.851881
Cole JE, Kassiteridi C, Monaco C. Toll-like receptors in atherosclerosis: a 'Pandora's box' of advances and controversies. Trends in Pharmacological Sciences. 2013 2014/12/01; 34(11): 629-36.
Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol. Jul; 30(7): 1282-92.
Gori AM, Cesari F, Marcucci R, Giusti B, Paniccia R, Antonucci E, et al. The balance between pro- and antiinflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients. Atherosclerosis. 2009 Jan; 202(1): 255-62. http://dx.doi.org/10.1016/j.atherosclerosis.2008.04.001
Manthey HD, Zernecke A. Dendritic cells in atherosclerosis: functions in immune regulation and beyond. Thromb Haemost. 2012 Nov; 106(5): 772-8. http://dx.doi.org/10.1160/TH11-05-0296
Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther. 2009 Feb; 23(1): 31-40. http://dx.doi.org/10.1007/s10557-008-6147-2
Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med. 2002 Nov; 8(11): 1211-7. http://dx.doi.org/10.1038/nm1102-1211
Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis. 1989 Nov-Dec; 9(6): 908-18. http://dx.doi.org/10.1161/01.ATV.9.6.908
Olin-Lewis K, Krauss RM, La Belle M, Blanche PJ, Barrett PH, Wight TN, et al. ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. J Lipid Res. 2002 Nov; 43(11): 1969- 77. http://dx.doi.org/10.1194/jlr.M200322-JLR200
Hevonoja T, Pentikainen MO, Hyvonen MT, Kovanen PT, Ala-Korpela M. Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. Biochim Biophys Acta. 2000 Nov 15; 1488(3): 189-210. http://dx.doi.org/10.1016/S1388-1981(00)00123-2
Riley E, Dasari V, Frishman WH, Sperber K. Vaccines in development to prevent and treat atherosclerotic disease. Cardiol Rev. 2008 Nov-Dec; 16(6): 288-300. http://dx.doi.org/10.1097/CRD.0b013e3181885933
Grundtman C, Wick G. The autoimmune concept of atherosclerosis. Curr Opin Lipidol. 2011 Oct; 22(5): 327-34. http://dx.doi.org/10.1097/MOL.0b013e32834aa0c2
Wick MC, Mayerl C, Backovic A, van der Zee R, Jaschke W, Dietrich H, et al. In vivo imaging of the effect of LPS on arterial endothelial cells: molecular imaging of heat shock protein 60 expression. Cell Stress Chaperones. 2008 Sep; 13(3): 275-85. http://dx.doi.org/10.1007/s12192-008-0044-2
Pastrana JL, Sha X, Virtue A, Mai J, Cueto R, Lee IA, et al. Regulatory T cells and Atherosclerosis. J Clin Exp Cardiolog. 2012 Oct 8; 2012(Suppl 12): 2.
Sherer Y, Shoenfeld Y. Mechanisms of Disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheum. 2006; 2(2): 99-106. http://dx.doi.org/10.1038/ncprheum0092
Foteinos G, Afzal AR, Mandal K, Jahangiri M, Xu Q. Antiheat shock protein 60 autoantibodies induce atherosclerosis in apolipoprotein E-deficient mice via endothelial damage. Circulation. 2005 Aug 23;112(8):1206-13.
Perschinka H, Mayr M, Millonig G, Mayerl C, van der Zee R, Morrison SG, et al. Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol. 2003 Jun 1; 23(6): 1060-5. http://dx.doi.org/10.1161/01.ATV.0000071701.62486.49
Mayr M, Metzler B, Kiechl S, Willeit J, Schett G, Xu Q, et al. Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis. Circulation. 1999 Mar 30; 99(12): 1560-6. http://dx.doi.org/10.1161/01.CIR.99.12.1560
Schett G, Xu Q, Amberger A, Van der Zee R, Recheis H, Willeit J, et al. Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest. 1995 Dec; 96(6): 2569-77. http://dx.doi.org/10.1172/JCI118320
Zhu J, Quyyumi AA, Rott D, Csako G, Wu H, Halcox J, et al. Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis. Circulation. 2001 Feb 27; 103(8): 1071-5. http://dx.doi.org/10.1161/01.CIR.103.8.1071
Huittinen T, Leinonen M, Tenkanen L, Manttari M, Virkkunen H, Pitkanen T, et al. Autoimmunity to human heat shock protein 60, Chlamydia pneumoniae infection, and inflammation in predicting coronary risk. Arterioscler Thromb Vasc Biol. 2002 Mar 1; 22(3): 431-7. http://dx.doi.org/10.1161/hq0302.104512
Burian K, Kis Z, Virok D, Endresz V, Prohaszka Z, Duba J, et al. Independent and joint effects of antibodies to human heatshock protein 60 and Chlamydia pneumoniae infection in the development of coronary atherosclerosis. Circulation. 2001 Mar 20; 103(11): 1503-8. http://dx.doi.org/10.1161/01.CIR.103.11.1503
Bason C, Corrocher R, Lunardi C, Puccetti P, Olivieri O, Girelli D, et al. Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis. Lancet. 2003 Dec 13; 362(9400): 1971-7. http://dx.doi.org/10.1016/S0140-6736(03)15016-7
Xu Q. Role of heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol. 2002 Oct 1; 22(10): 1547-59. http://dx.doi.org/10.1161/01.ATV.0000029720.59649.50
Mori Y, Kitamura H, Song QH, Kobayashi T, Umemura S, Cyong JC. A new murine model for atherosclerosis with inflammation in the periodontal tissue induced by immunization with heat shock protein 60. Hypertens Res. 2000 Sep; 23(5): 475-81. http://dx.doi.org/10.1291/hypres.23.475
Almanzar G, Ollinger R, Leuenberger J, Onestingel E, Rantner B, Zehm S, et al. Autoreactive HSP60 epitopespecific T-cells in early human atherosclerotic lesions. J Autoimmun. 2012 Aug 14. http://dx.doi.org/10.1016/j.jaut.2012.07.006
Frostegard J. Autoimmunity, oxidized LDL and cardiovascular disease. Autoimmun Rev. 2002 Aug; 1(4): 233-7. http://dx.doi.org/10.1016/S1568-9972(02)00059-9
Tornvall P, Waeg G, Nilsson J, Hamsten A, Regnstrom J. Autoantibodies against modified low-density lipoproteins in coronary artery disease. Atherosclerosis. 2003 Apr; 167(2): 347-53. http://dx.doi.org/10.1016/S0021-9150(03)00021-2
George J, Afek A, Gilburd B, Blank M, Levy Y, Aron-Maor A, et al. Induction of early atherosclerosis in LDL-receptordeficient mice immunized with beta2-glycoprotein I. Circulation. 1998 Sep 15; 98(11): 1108-15. http://dx.doi.org/10.1161/01.CIR.98.11.1108
Hasunuma Y, Matsuura E, Makita Z, Katahira T, Nishi S, Koike T. Involvement of beta 2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol. 1997 Mar; 107(3): 569-73. http://dx.doi.org/10.1046/j.1365-2249.1997.d01-948.x
Shah PK, Chyu KY, Fredrikson GN, Nilsson J. Immunomodulation of atherosclerosis with a vaccine. Nat Clin Pract Cardiovasc Med. 2005 Dec; 2(12): 639-46. http://dx.doi.org/10.1038/ncpcardio0372
Palinski W, Witztum JL. Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis. J Intern Med. 2000 Mar; 247(3): 371-80. http://dx.doi.org/10.1046/j.1365-2796.2000.00656.x
Toshima S-i, Hasegawa A, Kurabayashi M, Itabe H, Takano T, Sugano J, et al. Circulating Oxidized Low Density Lipoprotein Levels : A Biochemical Risk Marker for Coronary Heart Disease. Arterioscler Thromb Vasc Biol. 2000 October 1, 2000; 20(10): 2243-7.
Holvoet P, Vanhaecke J, Janssens S, Van de Werf F, Collen D. Oxidized LDL and Malondialdehyde-Modified LDL in Patients With Acute Coronary Syndromes and Stable Coronary Artery Disease. Circulation. 1998 October 13, 1998; 98(15): 1487-94.
Boyd HC, Gown AM, Wolfbauer G, Chait A. Direct evidence for a protein recognized by a monoclonal antibody against oxidatively modified LDL in atherosclerotic lesions from a Watanabe heritable hyperlipidemic rabbit. Am J Pathol. 1989 November 1, 1989; 135(5): 815-25.
Kato R, Mori C, Kitazato K, Arata S, Obama T, Mori M, et al. Transient increase in plasma oxidized LDL during the progression of atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2009 Jan; 29(1): 33-9. http://dx.doi.org/10.1161/ATVBAHA.108.164723
Itabe H, Obama T, Kato R. The Dynamics of Oxidized LDL during Atherogenesis. J Lipids. 2011; 2011: 418313. http://dx.doi.org/10.1155/2011/418313
Cavalca V, Minardi F, Scurati S, Guidugli F, Squellerio I, Veglia F, et al. Simultaneous quantification of 8-isoprostaglandin-F(2alpha) and 11-dehydro thromboxane B(2) in human urine by liquid chromatography-tandem mass spectrometry. Anal Biochem. 2010 Feb 15; 397(2): 168-74. http://dx.doi.org/10.1016/j.ab.2009.10.014
Napoli C, D'Armiento FP, Mancini FP, Postiglione A, Witztum JL, Palumbo G, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest. 1997 Dec 1; 100(11): 2680-90. http://dx.doi.org/10.1172/JCI119813
Palinski W, Horkko S, Miller E, Steinbrecher UP, Powell HC, Curtiss LK, et al. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein Edeficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest. 1996 Aug 1; 98(3): 800-14. http://dx.doi.org/10.1172/JCI118853
Palinski W, Tangirala RK, Miller E, Young SG, Witztum JL. Increased autoantibody titers against epitopes of oxidized LDL in LDL receptor-deficient mice with increased atherosclerosis. Arterioscler Thromb Vasc Biol. 1995 Oct; 15(10): 1569-76. http://dx.doi.org/10.1161/01.ATV.15.10.1569
Shaw PX, Horkko S, Chang MK, Curtiss LK, Palinski W, Silverman GJ, et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest. 2000 Jun; 105(12): 1731- 40. http://dx.doi.org/10.1172/JCI8472
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010 Apr 29; 464(7293): 1357-61. http://dx.doi.org/10.1038/nature08938
Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010; 5(7): e11765. http://dx.doi.org/10.1371/journal.pone.0011765
Ait-Oufella H, Kinugawa K, Zoll J, Simon T, Boddaert J, Heeneman S, et al. Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation. 2007 Apr 24; 115(16): 2168-77. http://dx.doi.org/10.1161/CIRCULATIONAHA.106.662080
Aprahamian T, Rifkin I, Bonegio R, Hugel B, Freyssinet JM, Sato K, et al. Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med. 2004 Apr 19; 199(8): 1121-31. http://dx.doi.org/10.1084/jem.20031557
Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005 Apr; 6(4): 345-52. http://dx.doi.org/10.1038/ni1178
von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005 Apr; 6(4): 338-44. http://dx.doi.org/10.1038/ni1180
Mallat Z, Tedgui A. Immunomodulation to combat atherosclerosis: the potential role of immune regulatory cells. Expert Opin Biol Ther. 2004 Sep; 4(9): 1387-93. http://dx.doi.org/10.1517/14712598.4.9.1387
Mallat Z, Ait-Oufella H, Tedgui A. Regulatory T-cell immunity in atherosclerosis. Trends Cardiovasc Med. 2007 May; 17(4): 113-8. http://dx.doi.org/10.1016/j.tcm.2007.03.001
Hansson GK, Nilsson J. Vaccination against atherosclerosis? Induction of atheroprotective immunity. Semin Immunopathol. 2009 Jun; 31(1): 95-101. http://dx.doi.org/10.1007/s00281-009-0151-x
Binder CJ, Horkko S, Dewan A, Chang MK, Kieu EP, Goodyear CS, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med. 2003 Jun; 9(6): 736-43. http://dx.doi.org/10.1038/nm876
Chyu KY, Nilsson J, Shah PK. Active and passive immunization for atherosclerosis. Curr Opin Mol Ther. 2007 Apr; 9(2): 176-82.
Gaofu Q, Jun L, Xiuyun Z, Wentao L, Jie W, Jingjing L. Antibody against cholesteryl ester transfer protein (CETP) elicited by a recombinant chimeric enzyme vaccine attenuated atherosclerosis in a rabbit model. Life Sci. 2005 Oct 7; 77(21): 2690-702. http://dx.doi.org/10.1016/j.lfs.2005.05.037
Hansson GK. Vaccination against atherosclerosis: science or fiction? Circulation. 2002 Sep 24; 106(13): 1599-601. http://dx.doi.org/10.1161/01.CIR.0000035275.64667.A3
Klingenberg R, Lebens M, Hermansson A, Fredrikson GN, Strodthoff D, Rudling M, et al. Intranasal Immunization With an Apolipoprotein B-100 Fusion Protein Induces AntigenSpecific Regulatory T Cells and Reduces Atherosclerosis. Arterioscler Thromb Vasc Biol. 2010 Feb 18.
Maron R, Sukhova G, Faria AM, Hoffmann E, Mach F, Libby P, 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 Sep 24; 106(13): 1708-15. http://dx.doi.org/10.1161/01.CIR.0000029750.99462.30
van Puijvelde GH, Hauer AD, de Vos P, van den Heuvel R, van Herwijnen MJ, van der Zee R, et al. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation. 2006 Oct 31; 114(18): 1968-76. http://dx.doi.org/10.1161/CIRCULATIONAHA.106.615609
van Puijvelde GH, van Es T, van Wanrooij EJ, Habets KL, de Vos P, van der Zee R, et al. Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol. 2007 Dec; 27(12): 2677-83. http://dx.doi.org/10.1161/ATVBAHA.107.151274
Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med. 2005 Apr; 11(4 Suppl): S45-53. http://dx.doi.org/10.1038/nm1213
Mayer L, Shao L. Therapeutic potential of oral tolerance. Nat Rev Immunol. 2004 Jun; 4(6): 407-19. http://dx.doi.org/10.1038/nri1370
Sakaguchi S, Setoguchi R, Yagi H, Nomura T. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in self-tolerance and autoimmune disease. Curr Top Microbiol Immunol. 2006; 305: 51-66. http://dx.doi.org/10.1007/3-540-29714-6_3
Kelsall BL, Leon F. Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease. Immunol Rev. 2005 Aug; 206: 132-48. http://dx.doi.org/10.1111/j.0105-2896.2005.00292.x
Min SY, Park KS, Cho ML, Kang JW, Cho YG, Hwang SY, et al. Antigen-induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer's patches during the induction of oral tolerance to type II collagen and suppress experimental collagen-induced arthritis. Arthritis Rheum. 2006 Mar; 54(3): 887-98. http://dx.doi.org/10.1002/art.21647
Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic aciddependent mechanism. J Exp Med. 2007 Aug 6; 204(8): 1757-64. http://dx.doi.org/10.1084/jem.20070590
Ameli S, Hultgardh-Nilsson A, Regnstrom J, Calara F, Yano J, Cercek B, et al. Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol. 1996 Aug; 16(8): 1074-9. http://dx.doi.org/10.1161/01.ATV.16.8.1074
Fredrikson GN, Hedblad B, Berglund G, Alm R, Ares M, Cercek B, et al. Identification of immune responses against aldehyde-modified peptide sequences in apoB associated with cardiovascular disease. Arterioscler Thromb Vasc Biol. 2003 May 1; 23(5): 872-8. http://dx.doi.org/10.1161/01.ATV.0000067935.02679.B0
Fredrikson GN, Lindholm MW, Ljungcrantz I, Soderberg I, Shah PK, Nilsson J. Autoimmune responses against the apo B-100 LDL receptor-binding site protect against arterial accumulation of lipids in LDL receptor deficient mice. Autoimmunity. 2007 Mar; 40(2): 122-30. http://dx.doi.org/10.1080/08916930601165107
Horkko S, Binder CJ, Shaw PX, Chang MK, Silverman G, Palinski W, et al. Immunological responses to oxidized LDL. Free Radic Biol Med. 2000 Jun 15; 28(12): 1771-9. http://dx.doi.org/10.1016/S0891-5849(00)00333-6
Schiopu A, Bengtsson J, Soderberg I, Janciauskiene S, Lindgren S, Ares MP, et al. Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis. Circulation. 2004 Oct 5; 110(14): 2047-52. http://dx.doi.org/10.1161/01.CIR.0000143162.56057.B5
Schiopu A, Frendeus B, Jansson B, Soderberg I, Ljungcrantz I, Araya Z, et al. Recombinant antibodies to an oxidized lowdensity lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice. J Am Coll Cardiol. 2007 Dec 11; 50(24): 2313-8. http://dx.doi.org/10.1016/j.jacc.2007.07.081
Shaw PX, Horkko S, Tsimikas S, Chang MK, Palinski W, Silverman GJ, et al. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol. 2001 Aug; 21(8): 1333-9. http://dx.doi.org/10.1161/hq0801.093587
Zhou X, Caligiuri G, Hamsten A, Lefvert AK, Hansson GK. LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis. Arterioscler Thromb Vasc Biol. 2001 Jan; 21(1): 108-14. http://dx.doi.org/10.1161/01.ATV.21.1.108
Uyttenhove C, Arendse B, Stroobant V, Brombacher F, Van Snick J. Development of an anti-IL-12 p40 auto-vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection. Eur J Immunol. 2004 Dec; 34(12): 3572-81. http://dx.doi.org/10.1002/eji.200425443
Rohn TA, Jennings GT, Hernandez M, Grest P, Beck M, Zou Y, et al. Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis. Eur J Immunol. 2006 Nov; 36(11): 2857-67. http://dx.doi.org/10.1002/eji.200636658
Lu X, Chen D, Endresz V, Xia M, Faludi I, Burian K, et al. Immunization with a combination of ApoB and HSP60 epitopes significantly reduces early atherosclerotic lesion in Apobtm2SgyLdlrtm1Her/J mice. Atherosclerosis. 2010 Oct; 212(2): 472-80. http://dx.doi.org/10.1016/j.atherosclerosis.2010.06.007
Lakshmi Mundkur RM, Vrushali Deshpande, Sonia Samson, Sagar Tarate, Meenakshi Varma, Hemapriya Sivanandan, Sneha TS, Xinjie Lu, and Vijay V Kakkar, . Comparison of oral tolerance to ApoB and HSP60 peptides in preventing atherosclerosis lesion formation in Apobtm2SgyLdlrtm1Her/J Mice. Journal of Vaccine. 2013; 2013(13).
Lu X, Xia M, Endresz V, Faludi I, Szabo A, Gonczol E, et al. Impact of multiple antigenic epitopes from ApoB100, hHSP60 and Chlamydophila pneumoniae on atherosclerotic lesion development in Apob(tm2Sgy)Ldlr(tm1Her)J mice. Atherosclerosis. 2012 Aug 18. http://dx.doi.org/10.1016/j.atherosclerosis.2012.07.021
Mundkur L, Mukhopadhyay R, Samson S, Varma M, Kale D, Chen D, et al. Mucosal Tolerance to a Combination of ApoB and HSP60 Peptides Controls Plaque Progression and Stabilizes Vulnerable Plaque in Apob(tm2Sgy)Ldlr(tm1Her)/J Mice. PLoS One. 2013; 8(3): e58364. http://dx.doi.org/10.1371/journal.pone.0058364
Klingenberg R, Lebens M, Hermansson A, Fredrikson GN, Strodthoff D, Rudling M, et al. Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigenspecific regulatory T cells and reduces atherosclerosis. Arterioscler Thromb Vasc Biol. 2010 May; 30(5): 946-52. http://dx.doi.org/10.1161/ATVBAHA.109.202671
Sasaki N, Yamashita T, Takeda M, Shinohara M, Nakajima K, Tawa H, et al. Oral anti-CD3 antibody treatment induces regulatory T cells and inhibits the development of atherosclerosis in mice. Circulation. 2009 Nov 17; 120(20): 1996-2005. http://dx.doi.org/10.1161/CIRCULATIONAHA.109.863431
Herbin O, Ait-Oufella H, Yu W, Fredrikson GN, Aubier B, Perez N, et al. Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2012 Mar; 32(3): 605-12. http://dx.doi.org/10.1161/ATVBAHA.111.242800
Ait-Oufella H, Salomon BL, Potteaux S, Robertson AK, Gourdy P, Zoll J, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006 Feb; 12(2): 178-80. http://dx.doi.org/10.1038/nm1343
Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007 Aug 6; 204(8): 1775-85. http://dx.doi.org/10.1084/jem.20070602
Fredrikson GN, Bjorkbacka H, Soderberg I, Ljungcrantz I, Nilsson J. 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 Dec; 264(6): 563-70. http://dx.doi.org/10.1111/j.1365-2796.2008.01995.x
Klingenberg R, Gerdes N, Badeau RM, Gistera A, Strodthoff D, Ketelhuth DF, et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest. 2013 Mar 1; 123(3): 1323-34. http://dx.doi.org/10.1172/JCI63891
Weirather J, Hofmann UD, Beyersdorf N, Ramos GC, Vogel B, Frey A, et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res. 2014 Jun 20; 115(1): 55-67. http://dx.doi.org/10.1161/CIRCRESAHA.115.303895
Grainger DJ. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis. Arterioscler Thromb Vasc Biol. 2004 Mar; 24(3): 399-404. http://dx.doi.org/10.1161/01.ATV.0000114567.76772.33
Carrier Y, Yuan J, Kuchroo VK, Weiner HL. Th3 Cells in Peripheral Tolerance. I. Induction of Foxp3-Positive Regulatory T Cells by Th3 Cells Derived from TGF-Î T CellTransgenic Mice. The Journal of Immunology. 2007 January 1, 2007; 178(1): 179-85.
Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky VE, et al. Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol. 2002 Jun 1; 22(6): 975-82. http://dx.doi.org/10.1161/01.ATV.0000019729.39500.2F
Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamate C, Merval R, et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001 Nov 9; 89(10): 930-4. http://dx.doi.org/10.1161/hh2201.099415
Kelsall BL. A focus on dendritic cells and macrophages as key regulators of mucosal immunity. Mucosal Immunol. 2008 Nov; 1(6): 423-4. http://dx.doi.org/10.1038/mi.2008.66
Choi JH, Cheong C, Dandamudi DB, Park CG, Rodriguez A, Mehandru S, et al. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity. 2011 Nov 23; 35(5): 819-31. http://dx.doi.org/10.1016/j.immuni.2011.09.014
Subramanian M, Thorp E, Hansson GK, Tabas I. Tregmediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest. 2013 Jan 2; 123(1): 179-88. http://dx.doi.org/10.1172/JCI64617
Mundkur L, Ponnusamy T, Philip S, Rao LN, Biradar S, Deshpande V, et al. Oral dosing with multi-antigenic construct induces atheroprotective immune tolerance to individual peptides in mice. Int J Cardiol. 2014 Jun 10. http://dx.doi.org/10.1016/j.ijcard.2014.06.001
