Atherosclerosis is a chronic inflammatory disease associated with the activation of both innate and adaptive immune responses. Minority populations and young women with systemic lupus erythematosus are particularly prone to the development of atherosclerosis. Recently, a unique group of T lymphocytes, called invariant natural killer T (iNKT) cells, have been implicated in atherogenesis and lupus. This Project will test the hypothesis that iNKT cells are chronically activated during hyperlipidemia and that this conversion is uniquely involved in regulating and/or modulating an inflammatory response that exacerbates atherosclerosis and dysregulates immunity. This hypothesis is based on key preliminary studies demonstrating that (a) iNKT cell numbers and functions are altered in spontaneously hyperlipidemic apoE-deficient (apoE-/-) mice;(b) iNKT cells of apoE-/- mice express phenotypic markers distinct from wild type iNKT cells, suggesting activation;(c) absence of iNKT cells in apoE-/- mice reduces atherosclerosis but aggravates lupus;and (d) specific activation of iNKT cells in vivo is proatherogenic but protects against lupus. Based on these findings, the overall objective of this Project is to characterize the immunoregulatory mechanism(s) by which iNKT cells promote lesion formation in the artery wall.
Our specific aims are to: (1) investigate the effects of hyperlipidemia and atherosclerosis on iNKT cell numbers and functions in apoE-/- mice;(2) investigate the role of cytokine production by iNKT cells and subsequent immune activation in atherosclerosis and (3) determine the role of iNKT cells in lupus-accelerated atherosclerosis. Relevance to Public Health: Coronary heart disease associated with atherosclerosis is the primary cause of mortality in the United States. At extremely high risk for suffering a fatal cardiac event are young women with lupus. Lupus-accelerated atherosclerosis is independent of cholesterol levels and is thought to be largely associated with autoimmune dysregulation. iNKT cells represent some of the most potent immune regulators. Therefore, understanding their significance in lupus and atherosclerosis will provide valuable insights for the future generation of immunotherapy to treat both lupus and heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089310-05
Application #
8111924
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Kirby, Ruth
Project Start
2007-09-25
Project End
2014-05-31
Budget Start
2011-07-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$383,750
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Wilhelm, Ashley J; Rhoads, Jillian P; Wade, Nekeithia S et al. (2015) Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice. Ann Rheum Dis 74:778-85
Anderson-Baucum, Emily K; Major, Amy S; Hasty, Alyssa H (2014) A possible secondary immune response in adipose tissue during weight cycling: The ups and downs of yo-yo dieting. Adipocyte 3:141-5
Covarrubias, Roman; Wilhelm, Ashley J; Major, Amy S (2014) Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells. PLoS One 9:e102236
Liu, Yan; Major, Amy S; Zienkiewicz, Jozef et al. (2013) Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. J Am Heart Assoc 2:e000093
Major, Amy S (2013) Expanding the therapeutic frontier in atherosclerosis. J Cardiovasc Pharmacol 62:237-8
Yu, Fang; Du, Fen; Wang, Yuzhen et al. (2013) Bone marrow deficiency of MCPIP1 results in severe multi-organ inflammation but diminishes atherogenesis in hyperlipidemic mice. PLoS One 8:e80089
van Leuven, Sander I; Mendez-Fernandez, Yanice V; Wilhelm, Ashley J et al. (2012) Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr(-/-) mice. Ann Rheum Dis 71:408-14
Gabriel, Curtis L; Smith, Patricia B; Mendez-Fernandez, Yanice V et al. (2012) Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus. Am J Physiol Endocrinol Metab 303:E1313-24
Méndez-Fernández, Yanice V; Major, Amy S (2012) Humanizing the problem of transplant vasculopathy. Arterioscler Thromb Vasc Biol 32:163-4
Wilhelm, Ashley J; Major, Amy S (2012) Accelerated atherosclerosis in SLE: mechanisms and prevention approaches. Int J Clin Rheumtol 7:527-539

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