ROLE OF T & B CELL STIMULATORY CYTOKINES IN SLE

该实验室的长期目标是确定T细胞机制 其在系统性狼疮中引发并延续体液自身免疫 红斑性狼疮（SLE）。 在这项资助中要检验的假设是， SLE的发作与CD4+T细胞的活化有关， 在T细胞和B细胞自发分泌细胞因子中 刺激活性。 在不存在CD8+T细胞的情况下，B的产生 细胞刺激性细胞因子持续，而T细胞刺激性细胞因子持续， 细胞因子如IL 2被下调。 本项目的总体目标 项目是定义T细胞亚群，其激活导致 体液自身免疫以及确定几个 细胞因子及其产生动力学在发展过程中的作用 自身免疫 为了实现这一目标，我们将使用一个良好的特点， T细胞驱动的SLE鼠模型，即，父母到F1模型 移植物抗宿主病（GVHD），其中SLE样疾病是在 注射供体菌株T后的正常、未辐照F1小鼠 细胞 该模型适用于T细胞增殖的动力学分析 亚群激活、连续细胞因子产生和免疫调节研究 在疾病活动的不同阶段进行干预。 此外，通过 将自身免疫性GVHD中获得的结果与 急性、致命的GVHD，我们将能够区分那些免疫系统的， 自身免疫性疾病的发生机制 这两种形式的GHVD都有。 这项建议的具体目标如下： 1)定义CD4+和CD8+T细胞在免疫系统中的各自作用。 自身免疫的发展。 2)将T细胞和B细胞刺激性细胞因子的动力学定义为 通过增加的细胞因子基因表达[IL 2、IL 4、IL 5、IL 10 和γ干扰素（IFNg），并通过测定自发细胞因子 生产（IL2、IL5和IFNg）。 细胞因子产生增加或基因 表达将进一步研究，以确定淋巴细胞 负责的子集以及它是供体还是宿主。 将测试体内B细胞活化的其他测量。 3)通过体内治疗阻断或改变SLE GVHD的表现 用单克隆抗体（mAb）阻断细胞因子的功能 (IL2、IL4、IFNg和IL5）或T细胞亚群（CD4+或CD8+）。 体内mAb 将在GVHD发作时给予，以确定mAb治疗是否可以 阻止疾病发展。 在以后的研究中，mAb将延迟至 SLE GVHD诱导后2周，以确定已建立的疾病是否可以 被逆转。

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.