Autoimmune regulation and TCR repertoire in SLE anti CD40L

SLE 抗 CD40L 中的自身免疫调节和 TCR 库

• 批准号: 6227079
• 负责人: Leonard Chess
• 金额: $ 20.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6227079
• 关键词: CD40 molecule; T lymphocyte; antigens; autoantigens; bioassay; biopsy; cell population study; clinical research; clinical trials; flow cytometry; human subject; kidney; monoclonal antibody; placebos; systemic lupus erythematosus

We hypothesize that there are four principal events in the development of SLE: (1) genes predisposing to SLE establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process of SLE: (2) previously tolerant autoreactive CD4 T cells: (3) regulatory mechanisms including the activation of TH1 and TH2 CD4+ T cell subsets as well as those involving CD8 T-cells fail, through processes such as clonal deletion or changes in the cytokine milieu and (4) injurious IgG autoantibodies develop through cognitive T-cell B-cell interactions and in concern with potentially self reactive T-cells induce tissue damage and disease. The overall aim of this grant is to study patients at different stages of SLE activity and to use the opportunity presented by an ongoing clinical trial of a humanized monoclonal antibody (moAb) to CD40L in systemic lupus erythematosis (SLE) to study the immunopathogenesis of SLE and the basic mechanisms of the therapeutic intervention in this disorder. In principle, interruption of the CD40 ligand-dependent pathway could down-modulate SLE activity by acting at the distal level of the cognitive T-B interaction involved in IgG autoantibody production or at the induction and regulation of autoreactive T-cell clones. These more proximal mechanisms for anti-CD40L treatment would diminish the number of autoreactive cells in the T cell repertoire. We propose to test hypotheses relating to both the immunopathogenesis of SLE and the basic mechanism of the therapeutic intervention using anti-CD40L treatment. Specifically our aims are: (1) To identify by PCR based spectratyping techniques and T cell receptor (TCR) sequencing, oligoclonal and putatively autoantigen-driven expansions of the CD4 alphabeta TCR repertoire in SLE patients compared with those treated with moAb to CD40L: (2) Identify changes in the T cell functional response to autoantigens including Ro, La. These functional studies will include assay of T-B interactions in T cell activation, tolerance and help assays and (3) directly study the regulatory interactions of TH1, TH2 cells as well as CD8+T cells in controlling the TCR repertoire in SLE during anti-CD40L treatment. In select patients we will directly study the function and repertoire of T cells at the site of inflammation (kidney) using HVS immortalization techniques.

我们假设 SLE 的发展过程中有四个主要事件：(1) 易患 SLE 的基因建立了一个 T 细胞库，能够识别 SLE 自身免疫过程中固有的自身肽：(2) 先前耐受的自身反应性 CD4 T 细胞： (3) 通过克隆删除或细胞因子变化等过程，包括 TH1 和 TH2 CD4+ T 细胞亚群以及涉及 CD8 T 细胞的激活在内的调节机制失效(4) 有害的 IgG 自身抗体通过认知 T 细胞 B 细胞相互作用而产生，并与潜在的自身反应性 T 细胞诱导组织损伤和疾病有关。该资助的总体目标是研究处于 SLE 活动不同阶段的患者，并利用正在进行的 CD40L 人源化单克隆抗体 (moAb) 在系统性红斑狼疮 (SLE) 中的临床试验提供的机会来研究 SLE 的免疫发病机制以及治疗干预这种疾病的基本机制。原则上，CD40配体依赖性途径的中断可以通过作用于参与IgG自身抗体产生或诱导和调节自身反应性T细胞克隆的认知T-B相互作用的远端水平来下调SLE活性。这些更近端的抗 CD40L 治疗机制将减少 T 细胞库中自身反应细胞的数量。我们建议测试与 SLE 的免疫发病机制和使用抗 CD40L 治疗的治疗干预的基本机制相关的假设。具体来说，我们的目标是：(1) 通过基于 PCR 的谱型分析技术和 T 细胞受体 (TCR) 测序，与接受 CD40L 抗体治疗的患者相比，识别 SLE 患者中 CD4 字母 TCR 库的寡克隆和推定自身抗原驱动的扩展：( 2) 识别 T 细胞对自身抗原（包括 Ro、La）功能反应的变化。这些功能研究将包括 T 细胞活化、耐受性和辅助测定中 T-B 相互作用的测定以及 (3)直接研究 TH1、TH2 细胞以及 CD8+T 细胞在抗 CD40L 治疗期间控制 SLE 的 TCR 库的调节相互作用。在选定的患者中，我们将使用 HVS 永生化技术直接研究炎症部位（肾脏）的 T 细胞的功能和全部功能。