? Diverse inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) share the manifestation of organ injury induced by activation of inflammatory pathways. A feature common to inflammatory diseases is the infiltration into tissues of blood-derived leukocytes, a phenomenon that requires specific leukocyte-endothelial cell interactions in the microcirculation. While many molecules important in leukocyte-endothelial interactions have been identified, the specific events operative in the recruitment of leukocytes to target organs remain incompletely understood. A greater understanding of these pathways has the potential to lead to the discovery of novel, specific, yet broad-spectrum therapeutic modalities. For example, it is unclear whether distinct leukocyte-endothelial interactions are operative in rheumatic diseases, or indeed in mediating the distinct organ manifestations in these diseases. Complete characterization of the mechanisms of leukocyte recruitment requires the direct examination of leukocyte-endothelial interactions in vivo. This is possible using the technique of intravital microscopy (IVM), which has now been applied to many tissues including skin, brain, and synovium. Strong preliminary data suggests the involvement of mediators such as nitric oxide (NO) and the cytokine macrophage migration inhibitory factor (MIF) in the modulation of leukocyte-endothelial interactions. The long-term objectives of this project are to expand understanding of the role of these and other mediators in the microcirculation in models of SLE and RA.
The specific aims of this project are to: ? ? (i) Examine the leukocyte-endothelial interactions in the pathogenesis of murine SLE. Using IVM, we will define the regulatory role of NO in the MRL/fas-lpr model of SLE. ? ? (ii) Examine the role of MIF in the regulation of leukocyte-endothelial interactions. WT and MIF-/- mice, as well as mice treated with anti-MIF mAb and recombinant MIF will be studied using IVM of the synovial and muscle microcirculations under conditions of antigen-driven inflammation. ? ? (iii) Examine the role of MIF in the modulation of leukocyte-endothelial interactions in the pathogenesis of murine SLE. Using rMIF, anti-MIF mAb, and anti-MIF small molecules, and by generating MRL/Ipr/MIF -/- mice, we will examine the role of MIF in the modulation of leukocyte-endothelial interactions in murine SLE. ? ?
