| The critical role of IFNalpha in the pathogenesis of systemic lupus erythematosus (SLE) has been highlighted in recent years. Previous studies have revealed profound influence of IFNalpha on the biological activities of a wide range of immune cells including monocytes, dendritic cells, T and B cells. However, the mechanism by which IFNalpha affects important immunological events in lupus and therefore promote the progress of disease is not entirely clear. In this thesis, using an adenovirus (Ad-IFNalpha) to deliver a transient overexpression of IFNalpha in New Zealand Black x New Zealand White (NZB/W) F1 mice, we demonstrated that IFNalpha induces the production of large amounts of short-lived plasma cells in the spleen and promotes murine lupus in a T cell dependent manner. IFNalpha induces a robust B7-CD28 dependent germinal center response in the mice, which gives rise to pathogenic IgG2a anti-dsDNA antibodies. However, the disruption of B7-CD28 signaling is not sufficient to prevent or delay the onset of lupus. Furthermore, IFNalpha accelerated lupus is associated with elevated serum BAFF levels and upregulation of TLR7 in the B cells. BAFF/APRIL, blockade, while having no effects on the production of pathogenic autoantibodies, delays the progress of lupus in our model.;We also demonstrated that triple therapy with cyclophosphamide (Cytoxan), anti-CD154 antibody and CTLA4-Ig induces remission of nephritis in Ad-IFNalpha treated NZB/W F1 mice with a similar efficacy as it does in conventional NZB/W F1 mice. However, IFNalpha treatment accelerates relapse in a dose dependent manner.;Finally we explored the potential of using a chemokine-binding glycoprotein G encoded by bovine herpes virus 5 (BHV5gG) as a multiple-chemokine inhibitor in a number of autoimmune/inflammatory disease models. We showed that although BHV5gG treatment does not affect the progress of murine lupus, it significantly inhibits peritoneal neutrophil infiltration in thioglycollate-induced peritonitis model and ameliorates joint inflammation in K/BxN serum transfer arthritis model. |
