Dissertation

Modulation of leukocyte homeostasis in atherosclerosis

Promotores: Prof.dr. E.A.L. Biessen, Prof.dr. T.J.C. van Berkel

Author: I.A. Medina Rodriguez
Date: 13 May 2014
Links: Thesis in Leiden Repository

Many of the recognition molecules and mechanisms involved in immune responses have no bias towards external stimuli, but also sense and respond to pathological and physiological changes of non infectious origin taking place within the body. Aiming at defining potential immuno-therapeutic strategies to treat human atherosclerosis, the focus of this work was the modulation of immune processes determinant of atherosclerosis lesion progression or cessation in mice, such as hematopoiesis, diapedesis and intravasation, leukocyte differentiation, cholesterol uptake apoptosis and cell survival. Modulation of these processes, by using bone marrow transplantation of hematopoietic stem cells with genetic deficiencies or over-expressing human or mouse engineered genes, demonstrated to alter the fate of atherosclerotic lesions at the balance between macrophage accumulation and lesion vulnerability versus resolution of inflammation and wound healing. This thesis demonstrates that processes responsible for the development and progression of atherosclerosis are dynamic and can be modulated to induce lesion stabilization and disease resolution. These results are promising for the development of novel therapeutics and challenge the current notion that atherosclerosis has a predetermined fate towards lesion vulnerability to rupture, which in humans results in thrombosis and clinical manifestations such myocardial infarction or stroke and sudden death.