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.
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