EXPERIMENTAL INDUCTION OF SLE BY ALTERED IA

通过改变 IA 实验诱导 SLE

• 批准号: 3156747
• 负责人: ROBERT A. EISENBERG
• 金额: $ 12.53万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3156747
• 关键词: B lymphocyte; T lymphocyte; antileukocyte isoantibody; autoantibody; autoantigens; autoimmune disorder; cell bank /registry; clone cells; enzyme linked immunosorbent assay; genetic strain; graft versus host disease; histocompatibility antigens; immunofluorescence technique; immunoglobulin G; immunoglobulin idiotypes; immunologic techniques; immunoregulation; laboratory mouse; leukocyte activation /transformation; major histocompatibility complex; minor histocompatibility loci; monoclonal antibody; mutant; orphan disease /drug; systemic lupus erythematosus

The objective of the current proposal is to investigate mechanisms of autoantibody production in an experimentally induced model of systemic lupus erythematosus. Most of the experiments will utilize a chronic graft-versus-host reaction between Ia/b congenic mice, C57BL/6 and bm12. In this model, abnormal T-cell help is supplied by alloreactive T cells. The specific aims of the current proposal are aimed at elucidating generally applicable immunoregulatory pathways that are essential for the production or control of autoantibodies. One set of experiments will deal with the specificity of T cell/B cell collaboration required for autoantibody production. Induction of chronic GVH in double congenic chimeras (Ia and Igh allotype) will determine whether the precursors of autoantibody forming cells must be specifically recognized by alloreactive T cells. In a related set of experiments, the basic alloreactive graft-versus- host model will be expanded with T cells reactive to immunoglobulin allotype (IgG2a/a) and with nonspecific T cells specifically targeted by monoclonal immunoglobulin heterodimers which can cross link the T-cell receptor and B-cell surface markers. The possibility that alloreactive T cells also recognize self-antigen in conjunction with foreign Ia will be tested by selecting T-cell clones in vitro. The allotype marker experiments will be performed for both anti-chromatin and Coombs specificity. A further set of experiments will investigate the special role of the IgG2A isotype in autoantibody production. Several protocols will be attempted for suppression of this isotype, and the subsequent effect on autoantibody production will be ascertained. Finally, a series of experiments will deal with mechanisms of down regulation of autoantibody production in the graft-versus-host model. Prospective recipient animals will be pre-immunized with alloreactive T-cell lines. The transferred T cells that persist in recipients will be quantitated and described using monoclonal antibody markers. The possibility of anti- idiotype control will be investigated. C57BL/6-nu/nu mice will permit the testing of the role of host T cells. All these studies will increase our understanding of potential mechanisms that can lead to generalized autoantibody production in human collagen vascular disease, such as systemic lupus erythematosus.

本提案的目的是调查 在实验中，自身抗体产生的机制 诱导的系统性红斑狼疮模型。 大部分 实验将利用慢性移植物抗宿主反应 Ia/B同系小鼠、C57 BL/6和bm 12之间的差异。 在该模型中， 异常的T细胞帮助由同种异体反应性T细胞提供。 的 本提案的具体目标是阐明 一般适用的免疫调节途径， 对自身抗体的产生或控制至关重要。 一组 许多实验将涉及T细胞/B细胞的特异性 自身抗体生产所需的协作。 诱导 双同源嵌合体（Ia和Igh同种异型）中的慢性GVH将 确定自身抗体形成细胞的前体是否 必须被同种异体反应性T细胞特异性识别。 中 相关的一组实验，基本的同种异体反应性移植物对 宿主模型将用T细胞进行扩增， 免疫球蛋白同种异型（IgG 2a/a）和非特异性T细胞 被单克隆免疫球蛋白异二聚体特异性靶向 它可以交联T细胞受体和B细胞表面 标记。 同种异体反应性T细胞也能识别 自身抗原与外源Ia的结合将通过以下方法进行检测： 体外选择T细胞克隆。 同种异型标记实验 将对抗染色质和Coombs进行 的特异性 进一步的一组实验将研究 IgG 2A同种型在自身抗体产生中的特殊作用。 将尝试几种方案来抑制这种情况 同种型，随后对自身抗体产生的影响将 确定。 最后，一系列的实验将处理 自身抗体产生的下调机制 移植物抗宿主模型 预期受体动物将 用同种异体反应性T细胞系预免疫。 转移的T 将对在接受者中持续存在的细胞进行定量和描述 使用单克隆抗体标记。 反的可能性- 将研究独特型控制。 C57 BL/6-nu/nu小鼠将 允许测试宿主T细胞的作用。 所有这些研究 将增加我们对潜在机制的理解， 导致在人胶原中产生普遍自身抗体 血管疾病，如系统性红斑狼疮。