ANALYSIS OF IMMUNOREGULATORY DEFECT IN MRL/LPR MICE

MRL/1小鼠有一种罕见的干细胞缺陷，可以表现为 本身，取决于条件，在淋巴增殖物中 狼疮样综合征或运行中的移植物抗宿主综合征。 自身免疫与许多自体免疫的产生有关 抗体特异性，包括极高滴度的抗- 免疫球蛋白抗体，称为类风湿因子(RF)。这个 拟议的研究涉及4个主要问题，涉及 MRL/1模型：1)什么是必要的因素是足够的 MRL/1小鼠大量T细胞的增殖特性 这种自身免疫环境是如何影响 正常干细胞的分化；2)靶细胞和 效应细胞参与MRL/1跑步综合征；3)什么 诱导MRL/1小鼠产生RF及其调节机制 其他B细胞并影响疾病进展；以及4)什么是 体细胞分裂在自身抗体产生中的作用？ 为了解决这些问题，“自身免疫x正常”嵌合体小鼠 将产生一种表型截然不同的混合物 正常干细胞和自身免疫干细胞在不同的环境中共同成熟 各种自身免疫环境。B细胞的活性将是 通过测量血清免疫球蛋白和自身抗体效价进行监测。T细胞 功能活性将在限制稀释培养中进行测量。 射频研究将涉及生产和分析 单克隆性RF来源于MRL/1和MRL/1回交小鼠。 体细胞突变的评估将通过测定比率和 特定生殖系基因的多样化方向 在自身免疫环境中受到抗原刺激后。 总体而言，这些研究应该有助于我们对 免疫调节途径。这项提议的结果是 最终应该会在临床上得到应用 控制自身免疫性疾病，如系统性红斑狼疮 红斑性和类风湿性关节炎以及某些形式 移植物抗宿主病。

MRL/1 mice have an unusal stem cell defect that can manifest itself, depending on conditions, in either a lymphoproliferative lupus-like syndrome or in a runting graft-versus-host syndrome. Autoimmunity is associated with production of many auto- antibody specificities including exceptionally high titers of anti- IgG antibody, referred to as rheumatoid factors (RF). The proposed study addressed 4 main questions pertaining to the MRL/1 model: 1) What factors are necessary are sufficent for the massive T cell lymphoproliferation characteristic of MRL/1 mice and how does this autoimmune environment affect the differentiation of normal stem cells; 2) What are the target and effector cells involved in the MRL/1 runting syndrome; 3) What elicits RF production in MRL/1 mice and how do RF regulate other B cells and influence disease progression; and 4) What is the role of somatic muation in the generation of autoantibodies? To approach these issues, "autoimmune x normal" chimeric mice will be produced in which a mixture of phenotypically distinct normal and autoimmune stem cells mature together in various kinds of autoimmune environments. B cell activity will be monitored by measuring serum Ig and autoantibody titers. T cell functional activity will be measured in limiting dilution cultures. The RF studies will involve the production and analysis of monoclonal RF derived from MRL/1 and MRL/1 backcross mice. Somatic mutation will be assessed by determining the rate and direction of diversification of a particular germline gene following antigen stimulation in an autoimmune environment. Overall these studies should contribute to our basic understanding of immunoregulatory pathways. The results of this proposal should eventually have clinical application with regard to the control of autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis as well as certain forms of graft-versus-host disease.