Universiteit Leiden

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Research project

Immunotherapy to limit atherosclerosis

Atherosclerosis is a chronic inflammatory disease, and vaccination may be an attractive method to induce long lasting protection against endogenous factors that contribute to the development of atherosclerosis. We have shown that for example vaccination against modified LDL or interleukin-12 limits the development of atherosclerosis. We also focus on the development of cellular immunotherapies to inhibit atherosclerosis, as we have shown using myeloid-derived suppressor cells and mesenchymal stem cells. Moreover, modulation of regulatory proteins of inflammation, including costimulatory pathways and cytokines, are explored as therapeutic strategies to prevent atherosclerosis.

Johan Kuiper

Atherosclerosis is a chronic autoimmune disease in which both innate and adaptive immune responses contribute to lesion growth and plaque instability. Infiltrates of T cells, macrophages and dendritic cells have been found in human lesions and during recent years, new insights have shown the importance of recruitment and activation of immune cells in atherosclerosis development.

In the past, we have established that vaccination against a number of targets, such as modified LDL, interleukin-12, VEGFR2 and CD99 reduces atherosclerosis. We are currently applying novel vaccination strategies, which may even more promising in inhibiting atherosclerosis. We have also shown that atherosclerosis-driving autoantigens, such as oxLDL and HSP60, generate pro-atherogenic T cells that contribute to disease development. Oral tolerance induction to oxLDL and HSP60 attenuates the initiation and progression of atherosclerosis through the induction of regulatory T cells. Recently, we have established that treatment with oxLDL-induced apoptotic dendritic cells can also limit atherosclerosis and enhance plaque stability by inducing tolerance. This is an excellent example of shifting the immune system to act anti-atherogenic, using the body’s own cells. We are currently further investigating cellular immunotherapy, which is one of the emerging therapeutic strategies to prevent or inhibit a number of diseases, as this uses cells from the patient to combat disease progression. We have for example established that mesenchymal stem cells are capable of reducing atherosclerosis, by not only affecting inflammatory responses but also by significantly reducing dyslipidemia. Recently, we have also established that myeloid-derived suppressor cells can reduce the development of atherosclerosis.

Moreover, modulation of proteins that regulate the inflammatory response, including costimulatory pathways and cytokines, are explored as therapeutic strategies to prevent atherosclerosis. For example, we have found that interruption of the OX40-OX40 ligand pathway using blocking antibodies caused regression of atherosclerosis. Also, induction of the atheroprotective Tregs via IL-2 complexes was seen to inhibit early atherogenesis and stabilize advances plaques.

Together, in this research theme we aim to identify novel immunologic targets and apply immunotherapy to inhibit or even prevent the development of atherosclerosis.


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