Lymphocyte-vessel Wall Interaction in the Atherosclerotic Plaque: A Role of Fractalkine and its CX3CR1 Receptor

We intend to investigate the influence of the recently discovered chemokine fractalkine (FKN) and its receptor CX3CR1 on T lymphocytes in the development of an acute coronary syndrome. T lymphocytes are part of a chronic inflammatory infiltrate in the atherosclerotic plaque which is responsible for the destabilisation of the plaque. This might result in plaque rupture and subsequent formation of an occluding thrombus causing e.g. an acute coronary syndrome. Experimental data show that FKN and its CX 3 CR1 receptor play a specific role in the recruitment of inflammatory cells to the atherosclerotic plaque. This role was confirmed in mice without the FKN receptor, which showed a diminished progression of atherosclerosis. In addition, genetic variations (polymorphisms) of the receptor in humans were associated with a change of cardiovascular risk in clinical studies. The goal of the proposed study is to elucidate the role of FKN and its receptor for T lymphocytes in the unstable atherosclerotic plaque. We hypothesize that the FKN receptor regulates accumulation of these pro-inflammatory cells in the lesion. The distribution of FKN and its receptor will be proven by flow cytometry and immunohistochemistry. Furthermore, we will focus on the role of FKN and its receptor in modulating the cytotoxic effect of T lymphocytes on plaque resident cells as well as their ability to activate other inflammatory cells. Functional changes will be examined by the use of cell culture and gene profiling. Understanding the inflammatory process in the atherosclerotic process will help to identify targets for an immunomodulatory therapy in the acute coronary syndrome.