Novel experimental therapies for atherosclerosis : a genomics based approach

Atherosclerosis is a progressive disease of the large arteries characterized by lipid deposition, inflammation, cell death and fibrosis and it is the major cause of death in the Western world. In this thesis new and experimental therapies against atherosclerosis are designed and tested. New targets for these therapies were identified by using a mouse model for atherosclerosis, the LDL receptor deficient mouse. We used micro-arrays to compare gene expression from mice with atherosclerosis to control mice and the following targets, all related to leukocyte migration and activation, were identified; CCR5, CXCR3, CD99, IL-16, OX-40 and CD127. Vaccines against CD99, IL-16 and CD127 were designed and tested. Specific antagonists of CCR5 and CXCR3 were used to block these molecules and a specific antibody against OX40 ligand was tested in LDL receptor deficient mice. The effects of these treatment strategies are described in the chapters of this thesis. In conclusion, modulation of leukocyte activation and migration provides an attractive possibility for future drug design in the field of atherosclerosis.LEI Universiteit LeidenNetherlands Heart Foundation J. E. Jurriaanse stichting LACDR Boehringer Ingelheim Universiteit LeidenLACD