ANALYSIS OF IMMUNOREGULATORY DEFECT IN MRL/LPR MICE

MRL/LPR 小鼠免疫调节缺陷分析

• 批准号: 3071300
• 负责人: Ann Marshak-Rothstein
• 金额: $ 5.27万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1991-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3071300
• 关键词: B lymphocyte; T lymphocyte; antiantibody; antibody formation; autoantibody; autoimmune disorder; autoradiography; bone marrow transplantation; cell transformation; clone cells; enzyme linked immunosorbent assay; flow cytometry; graft versus host disease; hematopoietic stem cells; histocompatibility antigens; hybridomas; immunogenetics; immunoglobulin G; immunoregulation; interleukin 2; interleukin 3; leukocyte activation /transformation; leukocyte disorder; leukopoiesis; mixed lymphocyte reaction test; monoclonal antibody; nephritis; newborn animals; radiation immunosuppression; radioimmunoassay; rheumatoid factor; spleen transplantation; splenectomy; systemic lupus erythematosus; tissue mosaicism

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.

MRL/1 小鼠具有不寻常的干细胞缺陷，可表现为 本身，取决于条件，无论是淋巴增殖性 狼疮样综合征或运行缓慢的移植物抗宿主综合征。 自身免疫与许多自身免疫物质的产生有关 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）。 这 拟议的研究解决了与 MRL/1 模型： 1) 哪些因素是充分必要的 MRL/1 小鼠的大量 T 细胞淋巴增殖特征 这种自身免疫环境如何影响 正常干细胞的分化； 2）目标是什么？ 参与 MRL/1 奔跑综合征的效应细胞； 3）什么 在 MRL/1 小鼠中引发 RF 产生以及 RF 如何调节 其他 B 细胞并影响疾病进展； 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 将产生表型不同的混合物 正常干细胞和自身免疫干细胞以多种方式共同成熟 各种自身免疫环境。 B 细胞活性为 通过测量血清 Ig 和自身抗体滴度进行监测。 T细胞 将在有限稀释培养物中测量功能活性。 射频研究将涉及生产和分析 来自 MRL/1 和 MRL/1 回交小鼠的单克隆 RF。 体细胞突变将通过确定速率和 特定种系基因的多样化方向 在自身免疫环境中进行抗原刺激后。 总的来说，这些研究应该有助于我们的基本理解 的免疫调节途径。 本提案的结果 最终应该会在临床上得到应用 控制自身免疫性疾病，例如系统性狼疮 红斑病和类风湿性关节炎以及某些形式 移植物抗宿主病。