Clinical atherosclerosis involves chronic low-grade inflammation, implicating immune mediators in cardiovascular disease (CVD). T lymphocytes comprise approximately 20 percent of the cells in the atheroma fibrous cap, and, although controversial, mice deficient in T cells develop smaller aortic lesions than immunocompetent animals. Cytokines are pleiotrophic factors that affect many different types of cells and have various biological effects. T cells can be categorized by the types of cytokines they produce. Th1 cells make IFN, IL-2 and TNF, whereas Th2 cells make IL-4, IL-6, and IL-10. Many factors influence Th cell bias and determine dominant subtype response. These include: the cytokine environment during Th0 cell activation, the type of antigen-presenting cell, its major histocompatibility complex (MHC) class II antigen haplotype, expression of accessory molecules such as B7-1/B7-2, the concentration and type of T cell epitope, and the presence of additional regulatory cells, such as natural killer cells and T lymphocytes expressing the T cell receptor. In many diseases, susceptibility or resistance corresponds to the dominance of either Th1 or Th2 cell responses. The applicant hypothesizes that in murine atherosclerosis, a Th1 cell bias confers susceptibility, whereas, a Th2 cell bias promotes resistance. The PI will confirm this hypothesis by modulating Th bias towards either the Th1 or Th2 phenotype using three distinct methods.
Specific Aim 1 will modulate immune deviation by exogenous administration of IL-12 (Th1-inducing) or IL-4 (Th2-inducing) cytokines or by using cytokine knockout mice.
Specific Aim 2 will use irradiation chimeric mice made between C57BL/6 strains transgenic for IA and IE class II MHC molecules. The MHC class II IA molecule is associated with a Th1 bias and atherosclerosis susceptibility, whereas, the IE molecule is associated with Th2 bias and CVD resistance.
Specific Aim 3 will investigate the role of CD4+ T cells in atherogenesis and evaluate whether these cells promote Th1 cell dominance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061346-01A1
Application #
2906523
Study Section
Pathology A Study Section (PTHA)
Project Start
1999-09-09
Project End
2003-08-31
Budget Start
1999-09-09
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Harper, Mary-Ellen; Antoniou, Andreas; Villalobos-Menuey, Elizabeth et al. (2002) Characterization of a novel metabolic strategy used by drug-resistant tumor cells. FASEB J 16:1550-7