Dendritic cells as a potential target for the development of an atherosclerosis vaccine.

Acute cardiovascular syndromes (e.g. myocardial infarction and stroke) are a major cause of morbidity and mortality in industrialized countries. They result from rupture and subsequent thrombosis of an atherosclerotic plaque that has built up in the wall of large and middle-sized arteries. Chronic inflammation, mediated by dendritic cells (DCs) drives the development of atherosclerosis. DCs are present in healthy arteries in areas predisposed to atherosclerotic plaque formation, and accumulate within plaques where they can be localized in close vicinity to T cells. Recent work has revealed important functions of DCs in regulating inflammatory and immune mechanisms in atherogenesis. In addition to antigen presentation to T-cells with subsequent activation, DCs themselves will secrete inflammatory cytokines (e.g. IL-12), further exacerbating atherosclerosis. Because of their unique properties (capable of inducing either immune responses or immune tolerance), DCs can be harnessed to suppress unwanted responses, in the form of vaccines. Vaccination strategies using DCs are currently being explored in various diseases. In fact, the approval of Provenge® (the first "DC vaccine" for prostate cancer) by the FDA in 2010 has paved the way for further development of DC vaccines. Our central hypothesis is that a vaccine-based approach to manage atherosclerotic cardiovascular disease is a potentially viable strategy. In fact, the first proof of concept that this approach could be very useful in combatting cardiovascular disease came very recently from the group of Goran Hansson. Treatment of mice with in vitro generated tolerogenic DCs attenuated atherosclerotic plaque development. However, these DCs have an unstable phenotype. Therefore, in this project we aim to (1) identify biomarkers for plaque DCs for targeted immunotherapy, (2) generate stable, tolerogenic DCs using RNA interference to suppress autologous T-cell activation and (3) study the effects of siRNA mediated DC targeted IL-12 silencing on atherosclerotic plaque progression and stability in mice.This research program is part of a global research effort to develop new therapeutic approaches for atherosclerotic plaque stabilization. Specifically, the current program aims to elucidate whether or not modulation of immune responses can stabilize atherosclerotic plaques.

Keywords:IMMUNE TOLERANCE, INFLAMMATORY DISEASE, ATHEROSCLEROSIS, DENDRITIC CELLS

Disciplines:Cardiac and vascular medicine, Immunology