Atherosclerosis
Volume 220, Issue 2 , Pages 329-336 , February 2012

Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells

  • Thore Dietrich

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
    • Corresponding Author InformationCorresponding author at: Department of Medicine – Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. Tel.: +49 30 4593 2522.
  • ,
  • Thomas Hucko

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
  • ,
  • Christiane Schneemann

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
  • ,
  • Marleen Neumann

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
  • ,
  • Andreas Menrad

      Affiliations

    • Genzyme Europe, Cambridge, UK
  • ,
  • Joerg Willuda

      Affiliations

    • Bayer Schering Pharma AG, Berlin, Germany
  • ,
  • Kirstin Atrott

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
  • ,
  • Dietger Stibenz

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
  • ,
  • Eckart Fleck

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
  • ,
  • Kristof Graf

      Affiliations

    • Department of Medicine – Cardiology, Deutsches Herzzentrum, Berlin, Germany
    • Department of Medicine, Jüdisches Krankenhaus, Berlin, Germany
    • These two authors contributed equally to this study.
  • ,
  • Hans D. Menssen

      Affiliations

    • Philogen, S.p.A., Siena, Italy
    • These two authors contributed equally to this study.

Received 13 April 2011 ,Revised 20 September 2011 ,Accepted 27 September 2011.

References 

  1. Frostegard J, Ulfgren AK, Nyberg P, et al. Cytokine expression in advanced human atherosclerotic plaques: cominancee of pro-inflammatory (Th1) an macrophage-stimulating cytokines. Atherosclerosis. 1999;145:33–43
  2. Laurat E, Poirier B, Tupin E, et al. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation. 2001;104:197–202
  3. Buono C, Binder CJ, Stavrakis G, et al. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:1596–1601
  4. Mor A, Planer D, Luboshits G, et al. Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:893–900
  5. Foks AC, Frodermann V, ter Borg M, et al. Differential effects of regulatory T cells on the initiation and regression of atherosclerosis. Atherosclerosis. 2011;218:53–60
  6. Sasaki N, Yamashita T, Takeda M, et al. Oral anti-CD3 antibody treatment induces regulatory T cells and inhibits the development of atherosclerosis in mice. Circulation. 2009;120:1996–2005
  7. Upadhya S, Mooteri S, Peckham N, Pai RG. Atherogeneic effect of interleukin-2 and antiatherogeneic effect of interleukin-2 antibody in apo-E-deficient mice. Angiology. 2004;55:289–294
  8. Brandenburg S, Takahashi T, de la Rosa M, et al. IL-2 induces in vivo suppression by CD4(+)CD25(+)Foxp3(+) regulatory T cells. European Journal of Immunology. 2008;38:1643–1653
  9. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. Journal of Experimental Medicine. 2005;201:723–735
  10. Zorn E, Nelson EA, Mohseni M, et al. IL-2 regulates FOXP3 expression in human CD4+ CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 2006;108:1571–1579
  11. Humrich JY, Morbach H, Undeutsch R, et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:204–209
  12. Ait-Oufella H, Salomon BL, Potteaux S, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nature Medicine. 2006;12:178–180
  13. 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
  14. Matter CM. Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin. Circulation Research. 2004;95:1225–1233
  15. Dietrich T, Perlitz C, Licha K, et al. ED-B fibronectin (ED-B) can be targeted using a novel single chain antibody conjugate and is associated with macrophage accumulation in atherosclerotic lesions. Basic Research in Cardiology. 2007;102:298–307
  16. Fiechter M, Frey K, Fugmann T, et al. Comparative in vivo analysis of the atherosclerotic plaque targeting properties of eight human monoclonal antibodies. Atherosclerosis. 2011;214:325–330
  17. Pini A, Viti F, Santucci A, et al. Design and use of a phage display library. Journal of Biological Chemistry. 1998;273:21769–21776
  18. Carnemolla B, Borsi L, Balza E, et al. Enhancement of the antitumor proprties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix. Blood. 2002;99:1659–1665
  19. Sauer S, Erba PA, Petrini M, et al. Expression of the oncofetal ED-B-containing fibronectin isoform in hematologic tumors enables ED-B-targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients. Blood. 2009;113:2265–2274
  20. Dietrich T, Hucko T, Bourayou R, et al. High resolution magnetic resonance imaging in atherosclerotic mice treated with ezetimibe. The International Journal of Cardiovascular Imaging. 2009;25:827–836
  21. Graf K, Dietrich T, Tachezy M, et al. Monitoring therapeutical intervention with ezetimibe using targeted near-infrared fluorescence imaging in experimental atherosclerosis. Molecular Imaging. 2008;7:68–76
  22. Johannsen M, Spitaleri G, Curigliano G, et al. The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma. European Journal of Cancer. 2010;46:2926–2935
  23. Assier E, Jullien V, Lefort J, et al. NK cells and polymorphnuclear neutrophils are both critical for IL-2 induced pulmonary vascular leak syndrome. Journal of Immunology. 2004;172:7661–7668
  24. de Boer OJ, van der Wal AC. FOXP3(+) regulatory T cells in vulnerable atherosclerotic plaques. International Journal of Cardiology. 2010;145:161
  25. Gogishvili T, Langenhorst D, Luhder F, et al. Rapid regulatory T-cell response prevents cytokine storm in CD28 superagonist treated mice. PloS One. 2009;4:e4643
  26. El Ridi R, Salem R, Wagih A. Influence of interleukine-2 and interferon-gamma in murine schistosomiasis. Cytokine. 2006;32:281–288
  27. Trogan E, Fayad ZA, Itskovich VV, et al. Serial studies of mouse atherosclerosis by in vivo magnetic resonance imaging detect lesion regression after correction of dyslipidemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1714–1719
  28. Shah PK, Yano J, Reyes O, et al. High-dose recombinant apolipoprotein A-I (Milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice: potential implications for acute plaque stabilization. Circulation. 2001;103:3047–3050
  29. Feig JE, Rong JX, Shamir R, et al. HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:7166–7171
  30. Mallat Z, Gojova A, Brun V, et al. Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2003;108:1232–1237

PII: S0021-9150(11)00956-7

doi: 10.1016/j.atherosclerosis.2011.09.050

Atherosclerosis
Volume 220, Issue 2 , Pages 329-336 , February 2012