Evaluating the therapeutic potential of CD40 in low-grade chronic inflammation

A chronic low-grade inflammatory process lies at the core of many prominent diseases in our society. These include atherosclerosis, the underlying cause of cardiovascular disease, as well as diabetes and abdominal aortic aneurysm (AAA). Many different immune cells play specific roles in the pathophysiology of these conditions and the interaction between these cells is crucial in driving inflammation. One of the main pathways by which immune cells communicate during inflammation is via the costimulatory dyad CD40-CD40L.
The aim of the studies in this thesis was to further evaluate the role of inflammation in the pathophysiology of atherosclerosis, obesity and AAA, and also to assess the therapeutic potential of CD40-CD40L signaling. We describe the effects of new drugs called TRAF-STOPs, targeted against CD40-TRAF6, a specific target in the interaction between CD40 and CD40L. We show that these drugs are effective in inhibiting the deleterious inflammatory state both in atherosclerosis and obesity, with minimal side-effects. Furthermore, we examined the role of CD40 signaling on B cells and dendritic cells in atherosclerosis and the role of CD40L in AAA.
Finally, this thesis contains multiple reviews describing the role and therapeutic potential of inflammation in atherosclerosis and obesity.