MMUNE MECHANISMS IN ATHEROSCLEROSIS PROJECT LEADER: Cornelia Weyand, M.D. CO-INVESTIGATOR: Jorg J. Goronzy, M.D. ABSTRACT Dendritic cells (DC) are sentinels that capture and process antigens to prime T cells. When positioned in chronic inflammatory tissue lesions, DC function as sensors of environmental cues and differentiate into """"""""immune instructors"""""""" that guide the development and maturation of T lymphocytes and monocytes into distinct effector classes. Two different DC subtypes, myeloid DC and plasmacytoid DC, populate the inflamed atherosclerotic plaque where they interact with T cells in the shoulder region. Each of the DC types is equipped with a distinct set of pattern recognition receptors, Toll-like receptors (TLR), through which they inspect the microenvironment for danger signals, such as pathogen-derived motifs, cellular debris, and modified metabolites (e.g. oxLDL). Ultimately, the original DC trigger and the DC type will determine the intensity, duration, and character of resulting immune responses. This application is designed to understand mechanistically the impact of selective TLR triggering on plaque-embedded DC and the functional consequences for T cell and macrophage differentiation, vascular smooth muscle cell (VSMC) fate, and stability of the atherosclerotic plaque. Given the position of DC at the top of the inflammatory cascade and the potential of tolerogenic DC to downregulate immune responses, we will explore molecular mechanisms through which plaque-residing DC can dampen plaque inflammation and restabilize the lesion. By using intact human carotid atheroma and SCID chimeras implanted with human atheroma, we will investigate in Specific Aim 1 how selective DC activation confers differential instruction of effector functions in plaque-infiltrating T cells and macrophages. Specifically, we will study the consequences of TLR-mediated DC triggering on T-cell recruitment and survival, commitment to the Th1 vs. Th17 effector class, induction of T-cell cytotoxicity and orchestration of tissue-injurious macrophage functions.
Specific Aim 2 is designed to investigate the hypothesis that DC stimulation ultimately regulates the fate of plaque VSMC. We will focus on induction of proinflammatory cytokines, metalloproteinases, NADPH oxidases, and expression of the death receptor DR5 as determinants of apoptosis sensitivity.
Specific Aim 3 is devoted to developing novel immunomodulatory therapies with the goal of suppressing plaque inflammation and instability. Building on preliminary data showing that ligation of CD80/CD86 with the soluble decoy receptor CTl_A4-lg induces tryptophan depletion in plaque tissue and suppresses cellular injury, we will target plaque-residing DC to turn them into tryptophan catabolizing and immunosuppressive cells. We will explore whether CTLA4-lg-mediated tissue protection results from direct inhibition of tissue-damaging effector cells or whether it involves generation and expansion of anti-inflammatory CD4+CD25h'9hFoxp3+ T regulatory (Treg) cells. Mechanistic experiments, making use of adoptive transfers in human atheroma-SCID chimeras, will address the role of the stress kinase GCN2 as a molecular mediator of Treg induction.

Public Health Relevance

Inflammation-mediated damage of the atherosclerotic plaque causes plaque rupture and results in sudden blockage of blood flow, heart attacks, and strokes. The current application investigates how cells of the immune system, namely dendritic cells, are activated and how they regulate this unique type of inflammation. In patient-derived atherosclerotic tissues, we will study how dendritic cells sense danger signals, such as infections, and how they instruct T cells and macrophages to turn into tissue-attacking cells. Finally, we will target dendritic cells in the atherosclerotic plaque and reeducate them into anti-inflammatory regulators, with the ultimate goal of developing novel therapeutic interventions suppressing inflammation and promoting stabilization of the atherosclerotic plaque

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Emory University
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