Understanding differences between acute and chronic infections is important for the development of therapies to cure chronic diseases. By following a bystander naive T cell population, I found that a dramatic sequestration of lymphocytes into secondary lymphoid tissues occurred early following acute LCMV Armstrong infection, though not following infection with the chronic LMCV strain, cl-13. I hypothesized that the lack of early sequestration during persistent LCMV cl-13 contributed to the establishment of the chronic infection. I discovered that transient administration of the sequestration drug FTY720 enhanced immunity and prevented the establishment of chronic LCMV. Additionally, I found that FTY720 treatment cleared a previously established cl-13 infection. FTY720 has no antiviral properties and its treatment led to immune mediated clearance that is dependent on CD4 T cells. The goal of this grant is to understand the immune enhancing effects of FTY720 and apply the findings toward developing therapies and vaccines for chronic diseases. I hypothesize that transient treatment with FTY720 directly alters the location and interaction of lymphocytes with APCs that leads to enhanced immune activation, while indirectly preventing the establishment of chronic infection and promoting immune memory formation. In this grant, I will study both the mechanism of FTY720 immune enhancement, and its application. The three aims are: 1) to understand the role of CD4+ T cells in the enhancement of CD8+ T cell function during FTY720 treatment. 2) To understand the effects of FTY720 on dendritic cells and macrophages during FTY720 treatment, and on the general maintenance of immune architecture. 3) To understand whether FTY720 can act as an immune adjuvant, and enhance immunity against weak vaccine antigens that do not invoke a robust innate immune rsponse. Using FTY720 as an immune enhancing therapy to clear persistent infections is relevent for human diseases such as HIV, hepatitis B virus, and hepatitis C virus. Understanding the mechanism of immune enhancement is key for development of appropriate therapies for persistent diseases and for developing targeted adjuvants for desired vaccine responses. These experiments will help determine the mechanisms of FTY720 mediated immune enhancement. ? ? ?
