PET imaging to monitor and study drug effects in liver disease and autoimmunity

Autoimmune diseases affect approximately eight percent of the American population; their prevalence has increased globally. There are at least eighty different autoimmune diseases that have been discovered to date, each of which have different etiopathologies, clinical presentations and treatment courses. Autoimmune diseases are marked by a stark decrease in the quality of life of those afflicted. Understanding the biological processes that cause and contribute to these diseases is crucial for development of new treatment strategies and regimens. Chapter one of this dissertation summarizes the etiology and current treatment options for MS, how positron emission tomography (PET) is used to image pathways implicated in autoimmune diseases and summarizes the role that the deoxyribonucleoside salvage pathway has in autoimmunity. Chapter two explores the role the deoxyribonucleoside salvage pathway plays in the development of symptoms in a mouse model of multiple sclerosis. In this chapter, I illustrate that by targeting dCK (deoxycytidine kinase), the rate-limiting enzyme of the salvage pathway, there is a diminishment of clinical symptoms in myelin proteolipid protein (PLP139-151) induced EAE mice. This demonstrates that the salvage pathway plays a vital role in the pathology of the disease and could also play a role in the pathology of other autoimmune diseases. Furthermore, I explored the mechanism by which the small-molecule dCK inhibitor TRE-515 blocks dCK activity in vitro and in vivo, and how this affects the activation induced proliferation of pathogenic immune cells in our disease model.In chapter three, we evaluated whether we could use PET to assess and characterize drug-induced liver injury in mice and predict which mice would succumb to liver failure and those that would not. In chapter four, we evaluated whether we could visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation using different PET radiotracers. Chapter five is a re