Evidence continues to accumulate that immunological mechanisms are of central importance in atherogenesis, consistent with our current understanding of atherosclerosis as a chronic inflammatory disease. Our lab first demonstrated that epitopes of oxidized LDL (OxLDL) were immunodominant within the atherosclerotic plaque and that immunization of animals with a model of OxLDL, malondialdehyde modified LDL (MDA-LDL), was atheroprotective. We also demonstrated that immunization with a model oxidized phospholipid analogue found in OxLDL also provided atheroprotection. This suggests that an appropriate immunization strategy could be developed to inhibit atherogenesis. However, immunization with modified autologous LDL would not be practical for large populations. To develop a generalized vaccine requires the identification of the oxidation-specific epitope(s) that provides the atheroprotective immunity, but the actual chemical moieties generated by MDA modification of LDL are complex. The overall goal of these studies is to improve our understanding of immune responses to OxLDL and to initiate the development of a vaccine approach for the amelioration of atherosclerosis. To accomplish this we will identify specific immunogenic oxidation-specific epitope(s) that provide atheroprotective immunity, which could then be formulated into one or more vaccine approaches. We will synthesize a panel of MDA-lysine derived adducts, and a panel of oxidized phospholipid derived adducts, and use these to screen murine and human sera to determine the immunodominant chemical moieties. We will determine which of these candidate epitopes occur in vivo in atherosclerotic lesions and select candidates to test for their ability to be atheroprotective in cholesterol-fed LDL receptor deficient mice. We will develop a synthetic single epitope immunization strategy to test the immunogenicity and atheroprotective properties of selected epitopes in mice and we will determine mechanisms by which successful immunotherapy occurs. This information will improve our understanding of immune responses to OxLDL and could lead to the development of an immunization strategy that could be applied widely to ameliorate the progression of atherosclerosis. Lay Abstract: The immune system plays an important role in the development of atherosclerosis. We are trying to develop a vaccine that could be used to help prevent the progression of atherosclerosis

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086559-04
Application #
7777834
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2007-02-10
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$442,003
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Gonen, Ayelet; Hansen, Lotte F; Turner, William W et al. (2014) Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine. J Lipid Res 55:2137-55
Perry, Heather M; Oldham, Stephanie N; Fahl, Shawn P et al. (2013) Helix-loop-helix factor inhibitor of differentiation 3 regulates interleukin-5 expression and B-1a B cell proliferation. Arterioscler Thromb Vasc Biol 33:2771-9
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Que, Xuchu; Widhopf 2nd, George F; Amir, Shahzada et al. (2013) IGHV1-69-encoded antibodies expressed in chronic lymphocytic leukemia react with malondialdehyde-acetaldehyde adduct, an immunodominant oxidation-specific epitope. PLoS One 8:e65203
Leibundgut, Gregor; Witztum, Joseph L; Tsimikas, Sotirios (2013) Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis. Curr Opin Pharmacol 13:168-79
Montano, Erica N; Boullier, Agn├Ęs; Almazan, Felicidad et al. (2013) Development and application of a nonradioactive binding assay of oxidized low-density lipoprotein to macrophage scavenger receptors. J Lipid Res 54:3206-14
van Dijk, Rogier A; Kolodgie, Frank; Ravandi, Amir et al. (2012) Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions. J Lipid Res 53:2773-90
Arai, Kiyohito; Orsoni, Alexina; Mallat, Ziad et al. (2012) Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia. J Lipid Res 53:1670-8

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