Roles of MIF and iNOS in SLE-associate inflammation

描述(由申请人提供)： 各种炎症性疾病，如系统性红斑狼疮(SLE)和类风湿性关节炎(RA)，都是由炎症通路激活引起的器官损伤的表现。炎症性疾病的一个共同特征是血液来源的白细胞渗透到组织中，这一现象需要微循环中特定的白细胞-内皮细胞相互作用。虽然已经确定了许多在白细胞-内皮相互作用中重要的分子，但在白细胞向靶器官募集过程中起作用的特定事件仍然不完全清楚。对这些途径的更好理解有可能导致发现新颖、特定但广谱的治疗方式。例如，目前尚不清楚不同的白细胞与内皮细胞的相互作用是否在风湿性疾病中起作用，或者确实在这些疾病中调节不同的器官表现。对白细胞募集机制的完整描述需要直接检查体内白细胞与内皮细胞的相互作用。使用活体显微镜(IVM)技术是可能的，该技术现在已被应用于包括皮肤、脑和滑膜在内的许多组织。强有力的初步数据表明，一氧化氮(NO)和细胞因子巨噬细胞移动抑制因子(MIF)等介质参与了白细胞-内皮细胞相互作用的调节。该项目的长期目标是扩大对这些和其他介质在SLE和RA模型微循环中的作用的理解。该项目的具体目标是： (I)研究小鼠系统性红斑狼疮发病机制中白细胞与内皮细胞的相互作用。使用IVM，我们将定义NO在SLE的MRL/FAS-LPR模型中的调节作用。 (Ii)研究MIF在调节白细胞-内皮细胞相互作用中的作用。WT和MIF-/-小鼠，以及用抗MIF单抗和重组MIF治疗的小鼠，将在抗原驱动的炎症条件下进行滑膜和肌肉微循环的IVM研究。 (3)探讨MIF在小鼠系统性红斑狼疮发病机制中对白细胞-内皮细胞相互作用的调节作用。利用RMIF、抗MIF单抗和抗MIF小分子，并通过建立MRL/IPR/MIF-/-小鼠，我们将研究MIF在调节小鼠SLE中白细胞-内皮相互作用中的作用。

DESCRIPTION (provided by applicant): 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.