Targeting T cell Subsets in Autoimmune Disease

自身免疫性疾病中的靶向 T 细胞亚群

• 批准号: 10398218
• 负责人: John H Stone
• 金额: $ 6.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398218
• 关键词: Apoptosis; Apoptotic; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biological Markers; Biology; Biopsy; Blood; CD28 gene; CD4 Positive T Lymphocytes; Cell Cycle Kinetics; Cell Death; Cell Wall; Cells; Centers of Research Excellence; Cessation of life; Characteristics; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical assessments; Collection; Color; Cytotoxic T-Lymphocytes; Data; Disease; Dose; Endothelial Cells; Event; FOXP3 gene; Fibroblasts; Fibrosis; Flare; Functional disorder; Funding; General Hospitals; Human; IgG4; In Situ; Inflammation; Inflammatory; Institutes; Interleukin 6 Receptor; Interleukin-1 beta; Interleukin-17; Investigation; Laboratories; Lesion; Link; Lymphocyte Subset; Maintenance; Massachusetts; Modeling; Multiple Myeloma; Myofibroblast; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Phenotype; Plasma; Population; Prednisone; Proteome; Randomized; Recurrent disease; Regimen; Regulatory T-Lymphocyte; Research; Research Institute; Research Personnel; Rheumatology; Role; Safety; Sampling; Scientist; Site; Smooth Muscle Myocytes; Systemic Scleroderma; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Temporal Arteries; Temporal Arteritis; Therapeutic; Time; Tissues; Toxic effect; Transforming Growth Factor beta; Translational Research; Transportation; Variant; Vascular Smooth Muscle; Withdrawal; Work; arm; base; biomarker discovery; biomarker performance; cohort; disorder risk; efficacy evaluation; health related quality of life; human model; human monoclonal antibodies; humanized monoclonal antibodies; innovation; instrument; interest; macrophage; novel; novel therapeutics; open label; peripheral blood; programs; prospective; serological marker; therapy design; tocilizumab; transcriptome; translational medicine

The power of translational investigation has been exemplified by the Massachusetts General Hospital (MGH) Rheumatology/Ragon Institute research group. The group is comprised of clinical investigators from the MGH Rheumatology Division and basic scientists at the Ragon Institute of the MGH, MIT, and Harvard. Both IgG4-related disease (IgG4-RD) and giant cell arteritis (GCA) have been major clinical interests. We have described many of the clinical, pathological, and treatment characteristics of IgG4-RD and developed instruments to facilitate its study. We have also developed a detailed pathophysiological model and identified SLAM-F7 as a marker expressed on cells critical to IgG4-RD pathophysiology: a CD4+ cytotoxic T cell (CTL) and several types of B cells. We have phenotyped this CD4+CTL and the B cells with which it interacts, building a powerful case for the efficacy of an anti-SLAMF7 approach to treatment. Elotuzumab, approved in multiple myeloma, is a humanized monoclonal antibody that targets SLAM-F7. The Primary Clinical Project is a clinical trial program of elotuzumab in IgG4-RD, linked to robust mechanistic studies. Parallel with this work, we have led a worldwide trial of interleukin-6 receptor (IL6R) blockade in GCA that resulted in the worldwide approval of tocilizumab for that disease. Basic studies performed in our laboratories have demonstrated that GCA patients have an expanded population of inflammatory regulatory CD4+ T cells (Tregs) in their blood. These cells express markers of effector CD4+ T cells, produce IL-17, and carry a hypofunctional variant of the master regulatory factor Foxp3. The Alternate Clinical Project is a multi- center, two-arm, randomized, open-label clinical trial that will evaluate the efficacy and safety of IL-6 receptor blockade maintenance versus discontinuation in GCA. Patients will be followed longitudinally with careful clinical assessments to detect disease flares and capture clinical samples at the time of these events. We will investigate the roles of Tregs and other T cell subsets in both peripheral blood and at sites of disease. The Collaborative Project is based on substantial preliminary work that supports a new model for human autoimmune fibrosis. Quantitative multi-color in situ data implicate the clonally-expanded CD4+CTLs originally described by our group in IgG4-RD as the drivers of both IgG4-RD and systemic sclerosis. These CD4+CTLs infiltrate fibrotic tissues, secrete IL-1β and TGF-β, and induce apoptotic death and overly- exuberant tissue remodeling. CD163+ MerTK+ macrophages, generally induced in the context of apoptosis, accumulate in IgG4-RD lesions, indirectly suggesting that T cell-induced apoptotic cell death precedes tissue remodeling in human model of autoimmune fibrosis. Efforts in this proposed ACE program will be facilitated by: 1) a well-organized and already highly- functional ACE Core; and, 2) the MGH Translational Medicine Group, an academic clinical research organization unique to MGH that comprises the ACE Funds Management Core.

马萨诸塞州总医院是翻译研究的典范 (MGH)流变学/Ragon研究所研究小组。该小组由临床研究人员组成， MGH流变学部门和MGH，麻省理工学院和哈佛Ragon研究所的基础科学家。两 IgG 4相关疾病（IgG 4-RD）和巨细胞动脉炎（GCA）已成为临床研究的热点。 我们已经描述了IgG 4-RD的许多临床、病理和治疗特征， 开发工具，以促进其研究。我们还开发了详细的病理生理模型， 将SLAM-F7鉴定为在对IgG 4-RD病理生理学至关重要的细胞上表达的标志物：CD 4+细胞毒性T细胞， 细胞（CTL）和几种类型的B细胞。我们已经对这种CD 4 +CTL和与之相关的B细胞进行了表型分析， 相互作用，为抗SLAMF 7治疗方法的功效建立了强有力的案例。埃罗妥珠单抗， 是一种靶向SLAM-F7的人源化单克隆抗体。主 临床项目是IgG 4-RD中elotuzumab的临床试验项目，与稳健的机制研究相关。 与此同时，我们还领导了一项全球性的GCA患者白细胞介素-6受体（IL 6 R）阻断试验 这导致了托珠单抗在全球范围内被批准用于治疗这种疾病。在我们的实验室进行的基础研究 实验室已经证明，GCA患者的炎性调节细胞群增加， 血液中的CD 4 + T细胞（Tcells）。这些细胞表达效应CD 4 + T细胞的标志物，产生IL-17， 携带主调节因子Foxp 3的功能低下变体。替代临床项目是一个多- 一项评价IL-6受体的疗效和安全性的中心、双臂、随机、开放标签临床试验 GCA中维持封锁与停止封锁。将对患者进行纵向随访， 临床评估，以检测疾病突发并在这些事件发生时采集临床样本。我们将 研究外周血和疾病部位中TcB和其他T细胞亚群的作用。 该合作项目是基于大量的初步工作，支持一个新的模式， 人类自身免疫性纤维化定量多色原位数据暗示克隆扩增的CD 4 + CTL 最初由我们的小组在IgG 4-RD中描述为IgG 4-RD和系统性硬化症的驱动因素。这些 CD 4 + CTL浸润纤维化组织，分泌IL-1β和TGF-β，并诱导凋亡性死亡和过度增殖。 旺盛的组织重塑CD 163 + MerTK+巨噬细胞，通常在细胞凋亡的情况下诱导， 在IgG 4-RD病变中积累，间接表明T细胞诱导的凋亡细胞死亡先于组织 自身免疫性纤维化的人类模型中的重塑。 在这个拟议的ACE计划的努力将促进：1）一个组织良好，已经高度- 功能ACE核心;和，2）MGH转化医学组，一个学术临床研究 MGH独有的组织，包括ACE基金管理核心。