Defining pathogenic B cell regulation and role in scleroderma-associated interstitial lung disease (SSc-ILD)

定义致病性 B 细胞调节及其在硬皮病相关间质性肺疾病 (SSc-ILD) 中的作用

基本信息

  • 批准号:
    MR/V030108/1
  • 负责人:
  • 金额:
    $ 34.49万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2021
  • 资助国家:
    英国
  • 起止时间:
    2021 至 无数据
  • 项目状态:
    未结题

项目摘要

Scleroderma (SSc) is a severe autoimmune disease with high risk of tissue damage leading to premature death. It has three main interlinking abnormalities: autoimmunity, inflammation and fibrosis of tissues and organs. These include blood vessels, lungs and the heart. The severity and extent to which these organs are affected vary among the patients. Notably, lung fibrosis contributes to the cause of death in approximately 50% of these patients. Involvement of the lung is strongly linked to the type of autoantibodies that are produced by autoreactive B cells. Findings from the two centres indicate that patients fail to purge these autoreactive B lymphocytes. Recent evidence suggests that targeting B lymphocytes improves patient outcome in particular those affected by lung fibrosis but it appears that this treatment only benefits a proportion of patients. There are now emerging biologic agents (tocilizumab and rituximab) and anti-fibrotic agents (nintedanib) that benefit patients with lung fibrosis at early and late stages of disease, respectively. I, therefore, propose that the disease-specific pathways that drive lung fibrosis in SSc differ for patients with different autoantibody specificities and at different stages of disease. By analogy, blocking the activation of specific B cells that express high levels of interleukin-6 as a key mediator of fibrosis appear to be beneficial in an autoimmune neurological condition (neuromyelitis optica) further supporting my proposed strategy in SSc as an antibody-driven disease. I will review patient groups at UCL that are treated with tocilizumab/rituximab to assess clinical characteristics that distinguish responders from non-responders for lung fibrosis. This will help me identify patient subgroups with lung fibrosis from whom I will obtain blood samples to isolate B cells before and after treatment with tocilizumab/rituximab. I will then have access to new laboratory techniques at QMUL that will provide exciting tools to evaluate the different populations of B cells in the bloods. The technique I propose to use has already been applied in rheumatoid arthritis and multiple sclerosis with remarkable success. This is a major step forward because this present application with modern scientific approaches will allow B cells to be studied at single cells levels for their origin and biological signatures in response to tocilizumab/rituximab treatment. This will define the distinct types of B cells, antibody signatures and the key mediators expressed by these cells from patients with different autoantibody subtypes and stage of disease, and further understanding of their potential importance in SSc lung fibrosis. From the analysis of these B cells, I expect to identify distinct cellular and antibody signature that will distinguish clinical responders from non-responders to the biologic agents pre-treatment. The data will be used to develop a new model to predict how B cells responses impact on overall disease outcome (specifically lung function) and on other cell types like fibroblasts that are directly involved in the scarring process in the lungs. Definition of the detailed properties and functions of B cells and their biologic signatures will have future implications in precision medicine by facilitating better targeted treatments and determine which of the emerging B cell-directed therapies for SSc will work best for lung fibrosis for an individual patient. This is vital considering the very high clinical burden of SSc and current variations in response to available drugs. As well as providing information about B cell immunology and impact on treatments, this study will also have wider implications on other common autoimmune or fibrotic diseases affecting the lungs including idiopathic pulmonary disease where B cells may interact in different ways with other cell types driving the disease, and that similar investigative or therapeutic approaches may be applicable.
硬皮病(SSc)是一种严重的自身免疫性疾病,具有导致过早死亡的组织损伤的高风险。它有三个主要的相互关联的异常:自身免疫,炎症和组织和器官的纤维化。这些器官包括血管、肺和心脏。这些器官受影响的严重程度和程度在患者之间存在差异。值得注意的是,肺纤维化是这些患者中约50%的死亡原因。肺受累与自身反应性B细胞产生的自身抗体类型密切相关。这两个中心的结果表明,患者未能清除这些自身反应性B淋巴细胞。最近的证据表明,靶向B淋巴细胞可改善患者的结局,特别是受肺纤维化影响的患者,但似乎这种治疗仅使一部分患者受益。目前有新兴的生物制剂(托珠单抗和利妥昔单抗)和抗纤维化药物(尼达尼布)分别在疾病的早期和晚期使肺纤维化患者受益。因此,我提出,在SSc中驱动肺纤维化的疾病特异性途径对于具有不同自身抗体特异性和处于不同疾病阶段的患者是不同的。通过类比,阻断表达高水平白细胞介素-6(作为纤维化的关键介质)的特定B细胞的活化似乎在自身免疫性神经病症(视神经肌萎缩症)中是有益的,进一步支持我提出的SSc作为抗体驱动的疾病的策略。我将回顾UCL接受托珠单抗/利妥昔单抗治疗的患者组,以评估区分肺纤维化应答者和非应答者的临床特征。这将帮助我确定肺纤维化患者亚组,我将在托珠单抗/利妥昔单抗治疗前后采集血液样本以分离B细胞。然后,我将有机会在QMUL获得新的实验室技术,这将提供令人兴奋的工具来评估血液中不同的B细胞群。我建议使用的技术已经应用于类风湿性关节炎和多发性硬化症,并取得了显著的成功。这是向前迈出的重要一步,因为采用现代科学方法的本申请将允许在单细胞水平上研究B细胞的起源和响应于托珠单抗/利妥昔单抗治疗的生物学特征。这将定义不同类型的B细胞、抗体特征和这些细胞表达的关键介质,这些细胞来自具有不同自身抗体亚型和疾病阶段的患者,并进一步了解它们在SSc肺纤维化中的潜在重要性。通过对这些B细胞的分析,我希望能够识别出不同的细胞和抗体特征,以区分生物制剂治疗前的临床应答者和非应答者。这些数据将用于开发一种新的模型,以预测B细胞反应如何影响整体疾病结果(特别是肺功能)以及其他细胞类型,如直接参与肺部瘢痕形成过程的成纤维细胞。对B细胞的详细性质和功能及其生物特征的定义将通过促进更好的靶向治疗并确定哪种新兴的针对SSc的B细胞治疗对个体患者的肺纤维化最有效而在未来的精准医学中产生影响。考虑到SSc的非常高的临床负担和目前对可用药物的反应变化,这是至关重要的。除了提供有关B细胞免疫学和对治疗影响的信息外,本研究还将对影响肺部的其他常见自身免疫性或纤维化疾病(包括特发性肺病)产生更广泛的影响,其中B细胞可能以不同方式与其他细胞类型相互作用,从而导致疾病,并且类似的研究或治疗方法可能适用。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
P153 Rituximab and tocilizumab and their effect on lung disease progression in scleroderma: a retrospective cohort study at a single centre
P153 利妥昔单抗和托珠单抗及其对硬皮病肺部疾病进展的影响:单中心回顾性队列研究
  • DOI:
    10.1093/rheumatology/kead104.194
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Goldman N
  • 通讯作者:
    Goldman N
Dysregulated B cell function and disease pathogenesis in systemic sclerosis.
  • DOI:
    10.3389/fimmu.2022.999008
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Beesley, Claire F.;Goldman, Nina R.;Taher, Taher E.;Denton, Christopher P.;Abraham, David J.;Mageed, Rizgar A.;Ong, Voon H.
  • 通讯作者:
    Ong, Voon H.
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Nina Goldman其他文献

Prospects for the power sector in nine developing countries
九个发展中国家电力行业的前景
  • DOI:
    10.1016/0301-4215(93)90262-e
  • 发表时间:
    1993
  • 期刊:
  • 影响因子:
    0
  • 作者:
    S. Meyers;S. Meyers;Nina Goldman;Nathan Martin;Rafael Friedmann
  • 通讯作者:
    Rafael Friedmann
Addressing loneliness and social isolation in 52 countries: a scoping review of National policies
  • DOI:
    10.1186/s12889-024-18370-8
  • 发表时间:
    2024-05-01
  • 期刊:
  • 影响因子:
    3.600
  • 作者:
    Nina Goldman;Devi Khanna;Marie Line El Asmar;Pamela Qualter;Austen El-Osta
  • 通讯作者:
    Austen El-Osta

Nina Goldman的其他文献

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