Co-stimulatory molecules in and beyond co-stimulation – tipping the balance in atherosclerosis?

 

PDF Download Buy Article Permissions and Reprints

Summary

A plethora of basic laboratory and clinical studies has uncovered the chronic inflammatory nature of atherosclerosis. The adaptive immune system with its front-runner, the T cell, drives the atherogenic process at all stages. T cell function is dependent on and controlled by a variety of either co-stimulatory or co-inhibitory signals. In addition, many of these proteins enfold T cell-independent pro-atherogenic functions on a variety of cell types. Accordingly they represent potential targets for immune- modulatory and/or anti-inflammatory therapy of atherosclerosis. This review focuses on the diverse role of co-stimulatory molecules of the B7 and tumour necrosis factor (TNF)-superfamily and their downstream signalling effectors in atherosclerosis. In particular, the contribution of CD28/CD80/CD86/CTLA4, ICOS/ICOSL, PD-1/PDL-1/2, TRAF, CD40/CD154, OX40/OX40L, CD137/CD137L, CD70/CD27, GITR/GITRL, and LIGHT to arterial disease is reviewed. Finally, the potential for a therapeutic exploitation of these molecules in the treatment of atherosclerosis is discussed.

• References

• 1 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6: 508-519.
  CrossrefPubMedGoogle Scholar
• 2 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
  CrossrefPubMedGoogle Scholar
• 3 Andersson J, Libby P, Hansson GK. Adaptive immunity and atherosclerosis. Clin Immunol 2010; 134: 33-46.
  CrossrefPubMedGoogle Scholar
• 4 Hartvigsen K, Chou MY, Hansen LF. et al. The role of innate immunity in atherogenesis. J Lipid Res 2009; 50: S388-393. Suppl
  CrossrefPubMedGoogle Scholar
• 5 Reardon CA, Blachowicz L, White T. et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21: 1011-1016.
  CrossrefPubMedGoogle Scholar
• 6 Stoneman V, Braganza D, Figg N. et al. Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques. Circ Res 2007; 100: 884-893.
  CrossrefPubMedGoogle Scholar
• 7 Zhou X, Nicoletti A, Elhage R. et al. Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 2000; 102: 2919-2922.
  CrossrefPubMedGoogle Scholar
• 8 Swirski FK, Pittet MJ, Kircher MF. et al. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci USA 2006; 103: 10340-10345.
  CrossrefPubMedGoogle Scholar
• 9 Hansson GK, Jonasson L, Lojsthed B. et al. Localization of T lymphocytes and macrophages in fibrous and complicated human atherosclerotic plaques. Atherosclerosis 1988; 72: 135-141.
  CrossrefPubMedGoogle Scholar
• 10 Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989; 135: 169-175.
  PubMedGoogle Scholar
• 11 Zhou X, Stemme S, Hansson GK. Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-E-deficient mice. Am J Pathol 1996; 149: 359-366.
  PubMedGoogle Scholar
• 12 Whitman SC, Ravisankar P, Elam H. et al. Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice. Am J Pathol 2000; 157: 1819-1824.
  CrossrefPubMedGoogle Scholar
• 13 Davenport P, Tipping PG. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 2003; 163: 1117-1125.
  CrossrefPubMedGoogle Scholar
• 14 George J, Shoenfeld Y, Afek A. et al. Enhanced fatty streak formation in C57BL/6J mice by immunization with heat shock protein-65. Arterioscler Thromb Vasc Biol 1999; 19: 505-510.
  CrossrefPubMedGoogle Scholar
• 15 George J, Afek A, Gilburd B. et al. Induction of early atherosclerosis in LDL-receptor-deficient mice immunized with beta2-glycoprotein I. Circulation 1998; 98: 1108-1115.
  CrossrefPubMedGoogle Scholar
• 16 Kol A, Sukhova GK, Lichtman AH. et al. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation 1998; 98: 300-307.
  CrossrefPubMedGoogle Scholar
• 17 Gurfinkel E, Bozovich G, Beck E. et al. Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes. The final report of the ROXIS Study. Eur Heart J 1999; 20: 121-127.
  CrossrefPubMedGoogle Scholar
• 18 O'Connor CM, Dunne MW, Pfeffer MA. et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. J Am Med Assoc 2003; 290: 1459-1466.
  CrossrefPubMedGoogle Scholar
• 19 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.
  CrossrefPubMedGoogle Scholar
• 20 Hermansson A, Ketelhuth DF, Strodthoff D. et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med 2010; 207: 1081-1093.
  CrossrefPubMedGoogle Scholar
• 21 Gotsman I, Sharpe AH, Lichtman AH. T-cell costimulation and coinhibition in atherosclerosis. Circulation Res 2008; 103: 1220-1231.
  CrossrefPubMedGoogle Scholar
• 22 Ait-Oufella H, Salomon BL, Potteaux S. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178-180.
  CrossrefPubMedGoogle Scholar
• 23 Takahashi T, Tagami T, Yamazaki S. et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192: 303-310.
  CrossrefPubMedGoogle Scholar
• 24 Leitner J, Grabmeier-Pfistershammer K, Steinberger P. Receptors and ligands implicated in human T cell costimulatory processes. Immunol Lett 2010; 128: 89-97.
  CrossrefPubMedGoogle Scholar
• 25 Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 2007; 13: 5271-5279.
  CrossrefPubMedGoogle Scholar
• 26 Dopheide JF, Sester U, Schlitt A. et al. Monocyte-derived dendritic cells of patients with coronary artery disease show an increased expression of costimulatory molecules CD40, CD80 and CD86 in vitro. Coron Artery Dis 2007; 18: 523-531.
  CrossrefPubMedGoogle Scholar
• 27 de Boer OJ, Hirsch F, van der Wal AC. et al. Costimulatory molecules in human atherosclerotic plaques: an indication of antigen specific T lymphocyte activation. Atherosclerosis 1997; 133: 227-234.
  CrossrefPubMedGoogle Scholar
• 28 Kim WJ, Kang YJ, Suk K. et al. Comparative analysis of the expression patterns of various TNFSF/TNFRSF in atherosclerotic plaques. Immunol Invest 2008; 37: 359-373.
  CrossrefPubMedGoogle Scholar
• 29 Lee TS, Yen HC, Pan CC. et al. The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 1999; 19: 734-742.
  CrossrefPubMedGoogle Scholar
• 30 Buono C, Pang H, Uchida Y. et al. B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 2004; 109: 2009-2015.
  CrossrefPubMedGoogle Scholar
• 31 Furukawa Y, Mandelbrot DA, Libby P. et al. Association of B7-1 co-stimulation with the development of graft arterial disease. Studies using mice lacking B7-1, B7-2, or B7-1/B7-2. Am J Pathol 2000; 157: 473-484.
  CrossrefPubMedGoogle Scholar
• 32 Niinisalo P, Oksala N, Levula M. et al. Activation of indoleamine 2,3-dioxygenase-induced tryptophan degradation in advanced atherosclerotic plaques: Tampere vascular study. Ann Med 2010; 42: 55-63.
  CrossrefPubMedGoogle Scholar
• 33 Yan S, Zhang Q, Cai M. et al. A novel model of portal vein transplantation in mice using two-cuff technique. Microsurgery 2007; 27: 569-574.
  CrossrefPubMedGoogle Scholar
• 34 Vinh A, Chen W, Blinder Y. et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 2010; 122: 2529-2537.
  CrossrefPubMedGoogle Scholar
• 35 Dong C, Juedes AE, Temann UA. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 2001; 409: 97-101.
  CrossrefPubMedGoogle Scholar
• 36 Vieira PL, Wassink L, Smith LM. et al. ICOS-mediated signaling regulates cytokine production by human T cells and provides a unique signal to selectively control the clonal expansion of Th2 helper cells. Eur J Immunol 2004; 34: 1282-1290.
  CrossrefPubMedGoogle Scholar
• 37 Nurieva R I, Duong J, Kishikawa H. et al. Transcriptional regulation of th2 differentiation by inducible costimulator. Immunity 2003; 18: 801-811.
  CrossrefPubMedGoogle Scholar
• 38 Lohning M, Hutloff A, Kallinich T. et al. Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J Exp Med 2003; 197: 181-193.
  CrossrefPubMedGoogle Scholar
• 39 Herman AE, Freeman GJ, Mathis D. et al. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 2004; 199: 1479-1489.
  CrossrefPubMedGoogle Scholar
• 40 Afek A, Harats D, Roth A. et al. A functional role for inducible costimulator (ICOS) in atherosclerosis. Atherosclerosis 2005; 183: 57-63.
  CrossrefPubMedGoogle Scholar
• 41 Gotsman I, Grabie N, Gupta R. et al. Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation 2006; 114: 2047-2055.
  CrossrefPubMedGoogle Scholar
• 42 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-548.
  CrossrefPubMedGoogle Scholar
• 43 Latchman Y, Wood CR, Chernova T. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2: 261-268.
  CrossrefPubMedGoogle Scholar
• 44 Gotsman I, Grabie N, Dacosta R. et al. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J Clin Invest 2007; 117: 2974-2982.
  CrossrefPubMedGoogle Scholar
• 45 Bu DX, Tarrio M, Maganto-Garcia E. et al. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol 2011; 31: 1100-1107.
  CrossrefPubMedGoogle Scholar
• 46 Lee J, Zhuang Y, Wei X. et al. Contributions of PD-1/PD-L1 pathway to interactions of myeloid DCs with T cells in atherosclerosis. J Mol Cell Cardiol 2009; 46: 169-176.
  CrossrefPubMedGoogle Scholar
• 47 Bishop GA. The multifaceted roles of TRAFs in the regulation of B-cell function. Nat Rev Immunol 2004; 4: 775-786.
  CrossrefPubMedGoogle Scholar
• 48 Ha H, Han D, Choi Y. TRAF-mediated TNFR-family signaling. Curr Protoc Immunol 2009; Chapterr 11: Unit11 9D.
  PubMed
• 49 Zirlik A, Bavendiek U, Libby P. et al. TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells. Arterioscler Thromb Vasc Biol 2007; 27: 1101-1107.
  CrossrefPubMedGoogle Scholar
• 50 Missiou A, Kostlin N, Varo N. et al. Tumor necrosis factor receptor-associated factor 1 (TRAF1) deficiency attenuates atherosclerosis in mice by impairing monocyte recruitment to the vessel wall. Circulation 2010; 121: 2033-2044.
  CrossrefPubMedGoogle Scholar
• 51 Missiou A, Rudolf P, Stachon P. et al. TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory cell recruitment and foam cell formation. Circulation Res 2010; 107: 757-766.
  CrossrefPubMedGoogle Scholar
• 52 Urbich C, Mallat Z, Tedgui A. et al. Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation. J Clin Invest 2001; 108: 1451-1458.
  CrossrefPubMedGoogle Scholar
• 53 Yamawaki H, Lehoux S, Berk BC. Chronic physiological shear stress inhibits tumor necrosis factor-induced proinflammatory responses in rabbit aorta perfused ex vivo. Circulation 2003; 108: 1619-1625.
  CrossrefPubMedGoogle Scholar
• 54 Luo D, Luo Y, He Y. et al. Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis. Am J Pathol 2006; 169: 1886-1898.
  CrossrefPubMedGoogle Scholar
• 55 Slevin M, Elasbali AB, Miguel Turu M. et al. Identification of differential protein expression associated with development of unstable human carotid plaques. Am J Pathol 2006; 168: 1004-1021.
  CrossrefPubMedGoogle Scholar
• 56 Miyahara T, Koyama H, Miyata T. et al. Inflammatory signaling pathway containing TRAF6 contributes to neointimal formation via diverse mechanisms. Cardiovasc Res 2004; 64: 154-164.
  CrossrefPubMedGoogle Scholar
• 57 Miyahara T, Koyama H, Miyata T. et al. Inflammatory responses involving tumor necrosis factor receptor-associated factor 6 contribute to in-stent lesion formation in a stent implantation model of rabbit carotid artery. J Vasc Surg 2006; 43: 592-600.
  CrossrefPubMedGoogle Scholar
• 58 Donners MM, Beckers L, Lievens D. et al. The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling. Blood 2008; 111: 4596-4604.
  CrossrefPubMedGoogle Scholar
• 59 Lutgens E, Lievens D, Beckers L. et al. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med 2010; 207: 391-404.
  CrossrefPubMedGoogle Scholar
• 60 Stachon P, Missiou A, Walter C. et al. Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans. PLoS One 2010; 5: e11589
  CrossrefPubMedGoogle Scholar
• 61 Schonbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cellular and molecular life sciences : CMLS 2001; 58: 4-43.
  CrossrefPubMedGoogle Scholar
• 62 Mach F, Schonbeck U, Sukhova GK. et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA 1997; 94: 1931-1936.
  CrossrefPubMedGoogle Scholar
• 63 Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res 2001; 89: 1092-1103.
  CrossrefPubMedGoogle Scholar
• 64 Lievens D, Eijgelaar WJ, Biessen EA. et al. The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thromb Haemost 2009; 102: 206-214.
  Article in Thieme ConnectPubMedGoogle Scholar
• 65 Mach F, Schonbeck U, Sukhova GK. et al. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998; 394: 200-203.
  CrossrefPubMedGoogle Scholar
• 66 Bavendiek U, Zirlik A, LaClair S. et al. Atherogenesis in mice does not require CD40 ligand from bone marrow-derived cells. Arterioscler Thromb Vasc Biol 2005; 25: 1244-1249.
  CrossrefPubMedGoogle Scholar
• 67 Lutgens E, Gorelik L, Daemen MJ. et al. Requirement for CD154 in the progression of atherosclerosis. Nat Med 1999; 5: 1313-1316.
  CrossrefPubMedGoogle Scholar
• 68 Schonbeck U, Sukhova GK, Shimizu K. et al. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci USA 2000; 97: 7458-7463.
  CrossrefPubMedGoogle Scholar
• 69 Lutgens E, Cleutjens KB, Heeneman S. et al. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci USA 2000; 97: 7464-7469.
  CrossrefPubMedGoogle Scholar
• 70 Smook ML, Heeringa P, Damoiseaux JG. et al. Leukocyte CD40L deficiency affects the CD25(+) CD4 T cell population but does not affect atherosclerosis. Atherosclerosis 2005; 183: 275-282.
  CrossrefPubMedGoogle Scholar
• 71 Lievens D, Zernecke A, Seijkens T. et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010; 116: 4317-4327.
  CrossrefPubMedGoogle Scholar
• 72 Nagasawa M, Zhu Y, Isoda T. et al. Analysis of serum soluble CD40 ligand (sCD40L) in the patients undergoing allogeneic stem cell transplantation: platelet is a major source of serum sCD40L. Eur J Haematol 2005; 74: 54-60.
  CrossrefPubMedGoogle Scholar
• 73 Cipollone F, Chiarelli F, Davi G. et al. Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control. Diabetologia 2005; 48: 1216-1224.
  CrossrefPubMedGoogle Scholar
• 74 Cipollone F, Ferri C, Desideri G. et al. Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty. Circulation 2003; 108: 2776-2782.
  CrossrefPubMedGoogle Scholar
• 75 Heeschen C, Dimmeler S, Hamm CW. et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348: 1104-1111.
  CrossrefPubMedGoogle Scholar
• 76 Schonbeck U, Varo N, Libby P. et al. Soluble CD40L and cardiovascular risk in women. Circulation 2001; 104: 2266-2268.
  CrossrefPubMedGoogle Scholar
• 77 Varo N, de Lemos JA, Libby P. et al. Soluble CD40L: risk prediction after acute coronary syndromes. Circulation 2003; 108: 1049-1052.
  CrossrefPubMedGoogle Scholar
• 78 Varo N, Vicent D, Libby P. et al. Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones. Circulation 2003; 107: 2664-2669.
  CrossrefPubMedGoogle Scholar
• 79 Lee WL, Lee WJ, Chen YT. et al. The presence of metabolic syndrome is independently associated with elevated serum CD40 ligand and disease severity in patients with symptomatic coronary artery disease. Metabolism 2006; 55: 1029-1034.
  CrossrefPubMedGoogle Scholar
• 80 Natal C, Restituto P, Inigo C. et al. The proinflammatory mediator CD40 ligand is increased in the metabolic syndrome and modulated by adiponectin. J Clin Endocrinol Metab 2008; 93: 2319-2327.
  CrossrefPubMedGoogle Scholar
• 81 Schernthaner GH, Kopp HP, Krzyzanowska K. et al. Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery. Eur J Clin Invest 2006; 36: 395-401.
  CrossrefPubMedGoogle Scholar
• 82 Missiou A, Wolf D, Platzer I. et al. CD40L induces inflammation and adipogenesis in adipose cells--a potential link between metabolic and cardiovascular disease. Thromb Haemost 2010; 103: 788-796.
  Article in Thieme ConnectPubMedGoogle Scholar
• 83 Poggi M, Jager J, Paulmyer-Lacroix O. et al. The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia 2009; 52: 1152-1163.
  CrossrefPubMedGoogle Scholar
• 84 Poggi M, Engel D, Christ A. et al. CD40L Deficiency Ameliorates Adipose Tissue Inflammation and Metabolic Manifestations of Obesity in Mice. Arterioscler Thromb Vasc Biol 2011; 31: 2251-2260.
  CrossrefPubMedGoogle Scholar
• 85 Andre P, Prasad KS, Denis CV. et al. CD40L stabilizes arterial thrombi by a beta3 integrin--dependent mechanism. Nat Med 2002; 8: 247-252.
  CrossrefPubMedGoogle Scholar
• 86 Leveille C, Bouillon M, Guo W. et al. CD40 ligand binds to alpha5beta1 integrin and triggers cell signaling. J Biol Chem 2007; 282: 5143-5151.
  CrossrefPubMedGoogle Scholar
• 87 Zirlik A, Maier C, Gerdes N. et al. CD40 ligand mediates inflammation independently of CD40 by interaction with Mac-1. Circulation 2007; 115: 1571-1580.
  CrossrefPubMedGoogle Scholar
• 88 Rub A, Dey R, Jadhav M. et al. Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function. Nature Immunol 2009; 10: 273-280.
  CrossrefPubMedGoogle Scholar
• 89 Sidiropoulos P I, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 2004; 13: 391-397.
  CrossrefPubMedGoogle Scholar
• 90 Kawai T, Andrews D, Colvin RB. et al. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000; 6: 114
  PubMedGoogle Scholar
• 91 Croft M, So T, Duan W. et al. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev 2009; 229: 173-191.
  CrossrefPubMedGoogle Scholar
• 92 So T, Croft M. Cutting edge: OX40 inhibits TGF-beta- and antigen-driven conversion of naive CD4 T cells into CD25+Foxp3+ T cells. J Immunol 2007; 179: 1427-1430.
  CrossrefPubMedGoogle Scholar
• 93 Xiao X, Kroemer A, Gao W. et al. OX40/OX40L costimulation affects induction of Foxp3+ regulatory T cells in part by expanding memory T cells in vivo. J Immunol 2008; 181: 3193-3201.
  CrossrefPubMedGoogle Scholar
• 94 Weinberg AD, Bourdette DN, Sullivan TJ. et al. Selective depletion of myelin-reactive T cells with the anti-OX-40 antibody ameliorates autoimmune encephalomyelitis. Nature Med 1996; 2: 183-189.
  CrossrefPubMedGoogle Scholar
• 95 Wang X, Ria M, Kelmenson PM. et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Gen 2005; 37: 365-372.
  CrossrefPubMedGoogle Scholar
• 96 van Wanrooij EJ, van Puijvelde GH, de Vos P. et al. Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) pathway attenuates atherogenesis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2007; 27: 204-210.
  CrossrefPubMedGoogle Scholar
• 97 Nakano M, Fukumoto Y, Satoh K. et al. OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization. Cardiovasc Res 2010; 88: 539-546.
  CrossrefPubMedGoogle Scholar
• 98 Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 2005; 23: 23-68.
  CrossrefPubMedGoogle Scholar
• 99 Vinay DS, Kwon BS. Role of 4-1BB in immune responses. Semin Immunol 1998; 10: 481-489.
  CrossrefPubMedGoogle Scholar
• 100 Wang C, Lin GH, McPherson AJ. et al. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 2009; 229: 192-215.
  CrossrefPubMedGoogle Scholar
• 101 Foell J, Strahotin S, O'Neil SP. et al. CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J Clin Invest 2003; 111: 1505-1518.
  CrossrefPubMedGoogle Scholar
• 102 Foell JL, Diez-Mendiondo B I, Diez OH. et al. Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance. Immunology 2004; 113: 89-98.
  CrossrefPubMedGoogle Scholar
• 103 Olofsson PS, Soderstrom LA, Wagsater D. et al. CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 2008; 117: 1292-1301.
  CrossrefPubMedGoogle Scholar
• 104 Jeon HJ, Choi JH, Jung IH. et al. CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice. Circulation 2010; 121: 1124-1133.
  CrossrefPubMedGoogle Scholar
• 105 Dongming L, Zuxun L, Liangjie X. et al. Enhanced levels of soluble and membrane-bound CD137 levels in patients with acute coronary syndromes. Clin Chim Acta 2010; 411: 406-410.
  CrossrefPubMedGoogle Scholar
• 106 Nolte MA, van Olffen RW, van Gisbergen KP. et al. Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol Rev 2009; 229: 216-231.
  CrossrefPubMedGoogle Scholar
• 107 van Olffen RW, de Bruin AM, Vos M. et al. CD70-driven chronic immune activation is protective against atherosclerosis. J Innate Immun 2010; 2: 344-352.
  CrossrefPubMedGoogle Scholar
• 108 Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?. Nat Rev Immunol 2003; 3: 609-620.
  CrossrefPubMedGoogle Scholar
• 109 Azuma M. Role of the glucocorticoid-induced TNFR-related protein (GITR)-GITR ligand pathway in innate and adaptive immunity. Crit Rev Immunol 2010; 30: 547-557.
  CrossrefPubMedGoogle Scholar
• 110 Nocentini G, Riccardi C. GITR: a modulator of immune response and inflammation. Adv Exp Med Biol 2009; 647: 156-173.
  PubMedGoogle Scholar
• 111 Ronchetti S, Nocentini G, Petrillo MG. et al. Glucocorticoid-Induced TNFR family Related gene (GITR) enhances dendritic cell activity. Immunol Lett 2011; 135: 24-33.
  CrossrefPubMedGoogle Scholar
• 112 Galuppo M, Nocentini G, Mazzon E. et al. The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice. Br J Pharmacol 2011; 162: 1186-1201.
  CrossrefPubMedGoogle Scholar
• 113 You S, Poulton L, Cobbold S. et al. Key role of the GITR/GITRLigand pathway in the development of murine autoimmune diabetes: a potential therapeutic target. PLoS One 2009; 4: e7848
  CrossrefPubMedGoogle Scholar
• 114 Cuzzocrea S, Nocentini G, Di Paola R. et al. Glucocorticoid-induced TNF receptor family gene (GITR) knockout mice exhibit a resistance to splanchnic artery occlusion (SAO) shock. J Leukoc Biol 2004; 76: 933-940.
  CrossrefPubMedGoogle Scholar
• 115 Cuzzocrea S, Ayroldi E, Di Paola R. et al. Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis. Faseb J 2005; 19: 1253-1265.
  CrossrefPubMedGoogle Scholar
• 116 Nocentini G, Cuzzocrea S, Bianchini R. et al. Modulation of acute and chronic inflammation of the lung by GITR and its ligand. Ann NY Acad Sci 2007; 1107: 380-391.
  CrossrefPubMedGoogle Scholar
• 117 Kim WJ, Bae EM, Kang YJ. et al. Glucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques. Immunology 2006; 119: 421-429.
  CrossrefPubMedGoogle Scholar
• 118 Mauri DN, Ebner R, Montgomery R I. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 1998; 8: 21-30.
  CrossrefPubMedGoogle Scholar
• 119 Lee WH, Kim SH, Lee Y. et al. Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinases. Arterioscler Thromb Vasc Biol 2001; 21: 2004-2010.
  CrossrefPubMedGoogle Scholar
• 120 Otterdal K, Smith C, Oie E. et al. Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes. Blood 2006; 108: 928-935.
  CrossrefPubMedGoogle Scholar
• 121 Sandberg WJ, Halvorsen B, Yndestad A. et al. Inflammatory interaction between LIGHT and proteinase-activated receptor-2 in endothelial cells: potential role in atherogenesis. Circ Res 2009; 104: 60-68.
  CrossrefPubMedGoogle Scholar
• 122 Lo JC, Wang Y, Tumanov AV. et al. Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science 2007; 316: 285-288.
  CrossrefPubMedGoogle Scholar
• 123 Celik S, Langer H, Stellos K. et al. Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium. Thromb Haemost 2007; 98: 798-805.
  Article in Thieme ConnectPubMedGoogle Scholar
• 124 Ridker PM, Danielson E, Fonseca FA. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008; 359: 2195-2207.
  CrossrefPubMedGoogle Scholar
• 125 Klingenberg R, Hansson GK. Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J 2009; 30: 2838-2844.
  CrossrefPubMedGoogle Scholar
• 126 Genovese MC, Becker JC, Schiff M. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. New Engl J Med 2005; 353: 1114-1123.
  CrossrefPubMedGoogle Scholar
• 127 Schiff M, Keiserman M, Codding C. et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008; 67: 1096-1103.
  CrossrefPubMedGoogle Scholar