ANALYSIS OF IMMUNOREGULATORY DEFECT IN MRL/LPR MICE

MRL/1小鼠具有异常的干细胞缺陷， 本身，取决于条件，在淋巴增生性 狼疮样综合征或矮小移植物抗宿主综合征。 自身免疫性与许多自身免疫性疾病的产生有关。 抗体特异性，包括异常高滴度的抗- IgG抗体，简称类风湿因子（RF）。 的 拟议的研究解决了有关的4个主要问题， MRL/1模型：1）什么因素是必要的，是足够的， MRL/1小鼠大量T淋巴细胞增殖特征 这种自身免疫环境是如何影响 正常干细胞的分化; 2）什么是靶点， 参与MRL/1 Runting综合征的效应细胞; 3）什么 MRL/1小鼠中的ERF产生以及RF如何调节 其他B细胞和影响疾病进展;和4）什么是 体细胞突变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”嵌合小鼠， 将产生其中表型上不同的 正常干细胞和自身免疫干细胞在不同的 各种自身免疫环境。 B细胞活性将 通过测量血清IG和自身抗体滴度来监测。 T细胞 在有限稀释培养物中测量功能活性。 RF研究将涉及以下内容的制作和分析： 来自MRL/1和MRL/1回交小鼠的单克隆RF。 体细胞突变将通过测定其发生率和 特定生殖系基因的多样化方向 在自身免疫环境中抗原刺激后。 总的来说，这些研究应该有助于我们的基本理解 免疫调节途径。 这一提议的结果 最终应该有临床应用， 控制自身免疫性疾病，如系统性狼疮 红斑和类风湿性关节炎以及某些形式的 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.