Induction of Oral Tolerance to Oxidized Low-Density Lipoprotein Ameliorates Atherosclerosis

Background— Oxidation of low-density lipoprotein (LDL) and the subsequent processing of oxidized LDL (oxLDL) by macrophages results in activation of specific T cells, which contributes to the development of atherosclerosis. Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis. Methods and Results— Tolerance to oxLDL and malondialdehyde-treated LDL (MDA-LDL) was induced in LDL receptor−/− mice fed a Western-type diet by oral administration of oxLDL or MDA-LDL before the induction of atherogenesis. Oral tolerance to oxLDL resulted in a significant attenuation of the initiation (30% to 71%; P<0.05) and progression (45%; P<0.05) of atherogenesis. Tolerance to oxLDL induced a significant increase in CD4+CD25+Foxp3+ cells in spleen and mesenteric lymph nodes, and these cells specifically responded to oxLDL with increased transforming growth factor-&bgr; production. Tolerance to oxLDL also increased the mRNA expression of Foxp3, CTLA-4, and CD25 in the plaque. In contrast, tolerance to MDA-LDL did not affect atherogenesis. Conclusions— OxLDL-specific T cells, present in LDL receptor−/− mice and important contributors in the immune response leading to atherosclerotic plaque, can be counteracted by oxLDL-specific CD4+CD25+Foxp3+ regulatory T cells activated via oral tolerance induction to oxLDL. We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis.

[1]  R. Flavell,et al.  Natural regulatory T cells control the development of atherosclerosis in mice , 2006, Nature Medicine.

[2]  A. Tedgui,et al.  Regulatory T cell responses: potential role in the control of atherosclerosis , 2005, Current opinion in lipidology.

[3]  J. Renauld,et al.  Blockade of Interleukin-12 Function by Protein Vaccination Attenuates Atherosclerosis , 2005, Circulation.

[4]  J. Witztum,et al.  Apoptotic Cells with Oxidation-specific Epitopes Are Immunogenic and Proinflammatory , 2004, The Journal of experimental medicine.

[5]  Jan Nilsson,et al.  Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis , 2004, Circulation.

[6]  Y. Shoenfeld,et al.  Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with beta 2-glycoprotein I. , 2004, Cardiovascular research.

[7]  A. Jevnikar,et al.  Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. Tipping,et al.  The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. , 2003, The American journal of pathology.

[9]  S. Akira,et al.  Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. , 2003, Cardiovascular research.

[10]  M. D’Elios,et al.  T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. Wahl,et al.  TGF-β: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression , 2003 .

[12]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[13]  P. Libby.  Inflammation in atherosclerosis , 2002, Nature.

[14]  Jacob George,et al.  Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions. , 2002, Journal of the American College of Cardiology.

[15]  P. Libby,et al.  Mucosal Administration of Heat Shock Protein-65 Decreases Atherosclerosis and Inflammation in Aortic Arch of Low-Density Lipoprotein Receptor-Deficient Mice , 2002, Circulation.

[16]  W. van Eden,et al.  Dynamics of mycobacterial HSP65-induced T-cell cytokine expression during oral tolerance induction in adjuvant arthritis. , 2002, Rheumatology.

[17]  A. Daugherty,et al.  IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E-/- mice. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[18]  M. Fishbein,et al.  Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor–Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes , 2002, Circulation research.

[19]  E. Toussirot.  Oral tolerance in the treatment of rheumatoid arthritis. , 2002, Current drug targets. Inflammation and allergy.

[20]  H. Weiner,et al.  Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. , 2002, International immunology.

[21]  J. Kuiper,et al.  Attenuation of atherogenesis by systemic and local adenovirus‐mediated gene transfer of interleukin‐10 in LDLr ‐/‐ Mice , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  H. Weiner,et al.  Activation of CD25+CD4+ Regulatory T Cells by Oral Antigen Administration1 , 2001, The Journal of Immunology.

[23]  W. Strober,et al.  Cell Contact–Dependent Immunosuppression by Cd4+Cd25+Regulatory T Cells Is Mediated by Cell Surface–Bound Transforming Growth Factor β , 2001, The Journal of experimental medicine.

[24]  T. V. van Berkel,et al.  Induction of Rapid Atherogenesis by Perivascular Carotid Collar Placement in Apolipoprotein E–Deficient and Low-Density Lipoprotein Receptor–Deficient Mice , 2001, Circulation.

[25]  G. Hansson,et al.  The Role of Adaptive Immunity in Atherosclerosis , 2000, Annals of the New York Academy of Sciences.

[26]  K. Williams,et al.  Atherosclerosis--an inflammatory disease. , 1999, The New England journal of medicine.

[27]  F. Shi,et al.  Mechanisms of nasal tolerance induction in experimental autoimmune myasthenia gravis: identification of regulatory cells. , 1999, Journal of immunology.

[28]  Wei Sha,et al.  Structural Identification by Mass Spectrometry of Oxidized Phospholipids in Minimally Oxidized Low Density Lipoprotein That Induce Monocyte/Endothelial Interactions and Evidence for Their Presence in Vivo * , 1997, The Journal of Biological Chemistry.

[29]  A. Friedman.  Induction of Anergy in Th1 Lymphocytes by Oral Tolerance. , 1996, Annals of the New York Academy of Sciences.

[30]  C. Janeway,et al.  Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  H. Weiner,et al.  Peripheral deletion of antigen-reactive T cells in oral tolerance , 1995, Nature.

[32]  J. Witztum,et al.  T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[33]  G. Hansson,et al.  Immune mechanisms in atherosclerosis. , 1994, Coronary artery disease.

[34]  G. Macpherson,et al.  Antigen acquisition by dendritic cells: intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo , 1993, The Journal of experimental medicine.

[35]  D. Melamed,et al.  Direct evidence for anergy in T lymphocytes tolerized by oral administration of ovalbumin , 1993, European journal of immunology.

[36]  J. Salonen,et al.  Autoantibody against oxidised LDL and progression of carotid atherosclerosis , 1992, The Lancet.

[37]  T. V. van Berkel,et al.  Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells. , 1991, The Journal of biological chemistry.

[38]  M. Sporn,et al.  Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth , 1986, The Journal of experimental medicine.

[39]  J. Mattingly.  Immunologic suppression after oral administration of antigen. III. Activation of suppressor-inducer cells in the Peyer's patches. , 1984, Cellular immunology.

[40]  C. E. West,et al.  Separation of plasma lipoproteins by density-gradient ultracentrifugation. , 1975, Analytical biochemistry.

[41]  S. Wahl,et al.  TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. , 2003, Cytokine & growth factor reviews.

[42]  H. Kolb,et al.  Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes. , 2002, Diabetes.

[43]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[44]  T. Macdonald.  Immunosuppression caused by antigen feeding II. Suppressor T cells mask Peyer's patch B cell priming to orally administered antigen , 1983, European journal of immunology.

[45]  N. Vaz,et al.  Cross-suppression of specific immune responses after oral tolerance. , 1981, Memorias do Instituto Oswaldo Cruz.