EXPERIMENTAL INDUCTION OF SLE BY ALTERED IA

当前提案的目标是调查 自身抗体产生机制的实验研究 诱导的系统性红斑狼疮模型。大多数 实验将利用慢性移植物抗宿主反应 Ia/b同源基因小鼠C57BL/6和bm12之间。在这个模型中， 异体反应性T细胞提供异常T细胞帮助。这个 当前提案的具体目的是为了澄清 普遍适用的免疫调节途径是 对产生或控制自身抗体是必不可少的。一套 的实验将涉及T细胞/B细胞的特异性 生产自身抗体需要协作。诱导 双同基因嵌合体(Ia和IgH同种异型)的慢性GVH 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。在一个 相关的一系列实验，基础同种异体移植物抗- 宿主模型将扩展为T细胞反应 免疫球蛋白同种异型(IgG2a/a)和非特异性T细胞 由单抗免疫球蛋白异源二聚体特异性靶向 它可以使T细胞受体和B细胞表面发生交联 记号笔。同种异体反应性T细胞也识别的可能性 与外源Ia结合的自身抗原将通过 体外筛选T细胞克隆。同种异型标记实验 将同时为抗染色质和库姆斯执行 专一性。另一组实验将调查 IgG2a亚型在自身抗体产生中的特殊作用。 将尝试几种协议来抑制这种情况 以及随后对自身抗体产生的影响 被确定了。最后，一系列实验将处理 自身抗体产生下调的机制研究进展 移植物抗宿主模型。未来的接受动物将是 用同种异体反应性T细胞系预免疫。被转移的T 存留在受者体内的细胞将被量化和描述 使用单抗标记物。可能会出现反 将对独特型控制进行调查。C57BL/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，这些机制可以 导致人胶原蛋白产生广泛性自身抗体 血管疾病，如系统性红斑狼疮。

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.