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.

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诸如克隆缺失或细胞因子环境变化和（4）有害IgG自身抗体的过程通过认知T细胞B细胞相互作用而发展，并且对潜在的自我反应性T细胞引起组织损伤和疾病的关注。这笔赠款的总体目的是在SLE活动的不同阶段研究患者，并利用正在进行的临床试验中的临床试验（MOAB）在全身性红斑狼疮（SLE）中对CD40L进行的临床试验（MOAB）来研究SLE的SLE的免疫原理和这种疾病的治疗机制。原则上，CD40配体依赖性途径的中断可以通过在IgG自身抗体产生涉及的认知T-B相互作用的远端作用或自身反应性T细胞克隆的诱导和调节来下调SLE活性。这些抗CD40L处理的近端机制将减少T细胞库中自动反应性细胞的数量。我们提议使用抗CD40L治疗来检验与SLE的免疫发病发生有关的假设和治疗干预的基本机制。具体而言，我们的目的是：（1）通过基于PCR的频谱技术和T细胞受体（TCR）测序，寡球体和推定的自动抗原驱动的扩展的CD4字母TCR prertoire在SLE SLE中的扩展与cd40l的治疗方法相比，在cd40l中使用了cd40l的响应，将其涵盖了这些功能，包括cd40l的响应率： T细胞激活，耐受性和帮助测定中T-B相互作用的测定，（3）直接研究TH1，Th2细胞以及CD8+T细胞的调节相互作用，以控制抗CD40L处理期间SLE的TCR库。在某些患者中，我们将使用HVS永生技术直接研究炎症部位（肾脏）T细胞的功能和曲目。