Summary
Mounting evidence supports that a newly identified regulatory T cell (Treg), CD4+LAP+ Treg, is associated with oral tolerance induction and following inhibition of atherosclerosis, but little is described about whether nasal tolerance to antigen likewise induces the novel Tregs production and the relevant antiatherosclerotic benefit. We investigated the effect of nasal administration of heat shock protein-60 (HSP60) on atherogenesis. HSP60 or phosphate buffer solution (PBS) was nasally administered to six-week-old male ApoE−/− mice. At the 10th week after the nasal administration, there was a significant decrease in atherosclerotic plaque areas of aortic roots in the HSP60-treated mice as compared with those in the PBS-treated mice. Atherosclerosis suppression was accompanied with a significant increase in CD4+LAP+ and CD4+CD25+Foxp3+ Tregs and a concurrently increased production of TGF-β in the HSP60-treated mice. The protective effect of HSP60 was offset by injection of anti-TGF-β antibody. It is concluded that nasal administration of HSP60 can inhibit atherosclerotic formation through immune tolerance which is established by Tregs depending on the induction of anti-inflammatory cytokine TGF-β. Immune tolerance induced by nasal administration of HSP60 may provide an alternative therapeutic method for atherosclerosis.
Similar content being viewed by others
References
Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med, 1999,340(2):115–126
Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 2005,352(16): 1685–1695
Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol, 2006,2(2):99–106
Montecucco F, Mach F. Atherosclerosis is an inflammatory disease. Semin Immunopathol, 2009,31(1):1–3
Benagiano M, D’Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol, 2005,174(10):6509–6517
Binder CJ, Chang MK, Shaw PX, et al. Innate and acquired immunity in atherogenesis. Nat Med, 2002,8(11):1218–1226
Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol, 2011,12(3):204–212
Xu Q, Wick G. The role of heat shock proteins in protection and pathophysiology of the arterial wall. Mol Med Today, 1996,2(9):372–379
Jorgensen C, Gedon E, Jaquet C, et al. Gastric administration of recombinant 65 kDa heat shock protein delays the severity of typeII collagen induced arthritis in mice. J Rheumatol, 1998,25(4):763–767
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(13):1708–1715
Harats D, Yacov N, Giburd B, et al. Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions. J Am Coll Cardiol, 2002,40(7):1333–1338
Cobelens PM, Heijnen CJ, Nieuwenhuis EE, et al. Treatment of adjuvant-induced arthritis by oral administration of mycobacterial Hsp65 during disease. Arthritis Rheum, 2000,43(12):2694–2702
Mallat Z, Ait-Oufella H, Tedgui A. Regulatory T cell responses: potential role in the control of atherosclerosis. Curr Opin Lipidol, 2005,16(5):518–524
de Kleer IM, Kamphuis SM, Rijkers GT, et al. The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum, 2003,48(7): 2001–2010
Prakken BJ, Samodal R, Le TD, et al. Epitope-specific immunotherapy induces immune deviation of proinflam matory T cells in rheumatoid arthritis. Proc Natl Acad Sci USA, 2004,101(12):4228–4233
van Eden W, van der Zee R, Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol, 2005,5(4):318–330
Faria AM, Weiner HL. Oral tolerance: therapeutic implications for autoimmune diseases. Clin Dev Immunol, 2006,13(2–4):143–157
Faria AM, Weiner HL. Oral tolerance. Immunol Rev, 2005,206:232–259
Ait-Oufella H, Salomon BL, Potteaux S, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med, 2006,12(2):178–180
Taleb S, Tedgui A, Mallat Z. Regulatory T-cell immunity and its relevance to atherosclerosis. J Intern Med, 2008,263(5):489–499
van Puijvelde GH, van Es T, van Wanrooij EJ, et al. Induction of oral tolerance to HSP60 or an HSP60peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol, 2007,27(12):2677–2683
Liu JQ, Bai XF, Shi FD, et al. Inhibition of experimental autoimmune encephalomyelitis in Lewis rats by nasal administration of encephalitogenic MBP peptides: synergistic effects of MBP 68–86 and 87–99. Int Immunol, 1998,10(8):1139–1148
Shi FD, Li H, Wang H, et al. Mechanisms of nasal tolerance induction in experimental autoimmune myasthenia gravis: identification of regulatory cells. J Immunol, 1999,162(10):5757–5763
Xiong Q, Li J, Jin L, et al. Nasal immunization with heat shock protein 65 attenuates atherosclerosis and reduces serum lipids in cholesterol-fed wild-type rabbits probably through different mechanisms. Immunol Lett, 2009,125(1):40–45
Vilskersts R, Liepinsh E, Mateuszuk L, et al. Mildronate, a regulator of energy metabolism, reduces atherosclerosis in apoE/LDLR−/− mice. Pharmacology, 2009,83(5):287–293
Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell, 2008,133(5):775–787
Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol, 1995,155(3):1151–1164
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(10):1232–1237
van Puijvelde GH, Hauer AD, de Vos P, et al. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation, 2006,114(18): 1968–1976
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(20):1996–2005
Steffens S, Burger F, Pelli G, et al. Short-term treatment with anti-CD3 antibody reduces the development and progression of atherosclerosis in mice. Circulation, 2006,114(18):1977–1984
Samsom JN. Regulation of antigen-specific regulatory T-cell induction via nasal and oral mucosa. Crit Rev Immunol, 2004,24(3):157–177
Ostroukhova M, Seguin-Devaux C, Oriss TB, et al. Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest, 2004,114(1):28–38
Wan YY. Regulatory T cells: immune suppression and beyond. Cell Mol Immunol, 2010,7(3):204–210
Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med, 2001,194(5):629–644
Author information
Authors and Affiliations
Corresponding author
Additional information
These authors contributed equally to this work.
Rights and permissions
About this article
Cite this article
Li, H., Ding, Y., Yi, G. et al. Establishment of nasal tolerance to heat shock protein-60 alleviates atherosclerosis by inducing TGF-β-dependent regulatory T cells. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 32, 24–30 (2012). https://doi.org/10.1007/s11596-012-0004-z
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-012-0004-z