T AND B CELL STIMULATORY CYTOKINES AND SLE

这个实验室的长期目标是确定T细胞的机制 在系统性红斑狼疮中启动和维持体液自身免疫 红斑狼疮(SLE)。这项拨款中要检验的假设是 系统性红斑狼疮的发病与CD4+T细胞的激活有关 T细胞和B细胞自发分泌细胞因子的研究 刺激活动。在没有CD8+T细胞的情况下，B细胞的产生 细胞刺激性细胞因子持续存在，而T细胞刺激性 白介素2等细胞因子表达下调。这一行动的总体目标是 项目是定义T细胞亚群，其激活会导致 体液自身免疫以及确定几种作用 细胞因子及其在细胞发育过程中的产生动力学 自身免疫力。为了实现这一目标，我们将使用一种很有特色的， T细胞驱动的系统性红斑狼疮小鼠模型--亲代转化F1模型 移植物抗宿主病(GVHD) 注射供体菌株T后的正常、未照射的F1小鼠 细胞。这个模型很好地用于T细胞的动力学分析 亚群激活、序贯细胞因子产生与免疫研究 在疾病活动的不同阶段进行干预。此外，通过 比较在自身免疫性移植物抗宿主病中获得的结果与在 急性致命性移植物抗宿主病，我们将能够区分这些免疫学 自身免疫性疾病发生的特殊机制 这两种形式的温室气体排放都是常见的。 这项建议有以下具体目标： 1)明确CD4+T细胞和CD8+T细胞在 自身免疫的发展。 2)T细胞和B细胞刺激性细胞因子的动力学定义为 通过增加细胞因子基因的表达来衡量[对于IL2、IL4、IL5、IL10 和干扰素(IFNG)及自发细胞因子的测定 生产(IL2、IL5和IFNG)。增加细胞因子的产生或基因 为了确定淋巴细胞的表达，还将进一步研究 负责的子集以及其来源是捐赠者还是宿主。 将测试体内B细胞激活的其他措施。 3)通过体内治疗阻断或改变SLE移植物抗宿主病的表现 用能阻断细胞因子功能的单抗 (IL2、IL4、IFNG和IL5)或T细胞亚群(CD4+或CD8+)。体内单抗 将在移植物抗宿主病开始时给予，以确定单抗治疗是否可以 阻碍疾病的发展。在以后的研究中，mAb将被推迟到 在SLE GVHD诱导后2周确定已建立的疾病是否可以 被颠倒。

The long-term goal of this laboratory is to define the T cell mechanisms which initiate and perpetuate humoral autoimmunity in systemic lupus erythematosus (SLE). The hypothesis to be tested in this grant is that the onset of SLE is associated with activation of CD4+T cells resulting in spontaneous secretion of cytokines with both T cell and B cell stimulatory activity. In the absence of CD8+T cells, production of B cell stimulatory cytokines continues whereas T cell stimulatory cytokines, such as IL2, are down-regulated. The overall aims of this project are to define the T cell subsets whose activation leads to humoral autoimmunity as well as to determine the role of several cytokines and their production kinetics during the development of autoimmunity. To achieve this goal, we will use a well characterized, T cell driven murine model of SLE i.e., the parent-into-F1 model of graft-vs-host disease(GVHD) in which SLE-like disease is induced in normal, unirradiated F1 mice following the injection of donor strain T cells. This model lends itself well to a kinetic analysis of T cell subset activation, sequential cytokine production, and a study of immune intervention at different stages of disease activity. Furthermore, by comparing the results obtained in autoimmune GVHD to those occurring in acute, lethal GVHD, we will be able to distinguish those immunologic mechanisms that are specific for the development of autoimmunity from those that are common to both forms of GHVD. This proposal has the following specific aims: 1) Define the respective roles of CD4+ and CD8+T cells in the development of autoimmunity. 2) To define the kinetics of T cell and B cell stimulatory cytokines as measured by increased cytokine gene expression [for IL2, IL4,IL5,IL10 and gamma interferon (IFNg) and by assays of spontaneous cytokine production (IL2,IL5 and IFNg). Increased cytokine production or gene expression will be studied further in order to determine the lymphocyte subset responsible as well as whether it is donor or host in origin. Additional measures of in vivo B cell activation will be tested. 3) To block or change manifestations of SLE GVHD by in vivo treatment with monoclonal antibodies (mAb) which block the function of cytokines (IL2,IL4,IFNg and IL5) or T cell subsets (CD4+ or CD8+). In vivo mAb will be given at the onset of GVHD to determine if mAb treatment can block disease development. In later studies, mAb will be delayed until 2 weeks after SLE GVHD induction to determine if established disease can be reversed.