Targeting T cell Subsets in Autoimmune Disease

翻译调查的力量以马萨诸塞州综合医院为例 (MGH)风湿病/拉贡研究所研究小组。该小组由来自 麻省理工学院、麻省理工学院和哈佛大学拉贡研究所的MGH风湿病科和基础科学家。两者都有 IgG4相关疾病(IgG4-RD)和巨细胞性动脉炎(GCA)一直是临床研究的重点。 我们描述了许多IgG4-RD和IgG4-RD的临床、病理和治疗特点 开发了促进其研究的工具。我们还开发了一个详细的病理生理模型和 SLAM-F7被鉴定为对IgG4-RD病理生理至关重要的细胞上表达的标志物：一种CD4+细胞毒性T细胞 细胞(CTL)和几种类型的B细胞。我们已经对这个CD4+CTL和它的B细胞进行了表型鉴定 相互作用，为抗SLAMF7治疗方法的有效性建立了强有力的案例。Elotuzumab， 被批准用于多发性骨髓瘤的是一种针对SLAM-F7的人源化单抗。初选 临床项目是elotuzumab在IgG4-RD中的临床试验计划，与强大的机制研究相联系。 在这项工作的同时，我们领导了一项在GCA中阻断白细胞介素6受体(IL6R)的全球试验 这导致了tocilizumab在全世界范围内被批准用于治疗这种疾病。基础研究在我们的 实验室已经证明，GCA患者具有更大的炎症调节人群 血液中的CD4+T细胞(Tregs)。这些细胞表达效应CD4+T细胞的标志，产生IL-17，并 携带主调控因子Foxp3的一个功能低下的变体。交替临床项目是一个多- 中心，双臂，随机，开放标签的临床试验，将评估IL-6受体的有效性和安全性 在GCA中，封锁维护与中断。将仔细地对患者进行纵向跟踪 在这些事件发生时进行临床评估，以检测疾病耀斑并捕获临床样本。我们会 研究Tregs和其他T细胞亚群在外周血和疾病部位的作用。 协作项目以大量前期工作为基础，支持以下新模式 人类自身免疫性纤维化。定量多色原位数据提示克隆扩增的CD4+CTL 最初由我们的研究小组在IgG4-RD中描述为IgG4-RD和系统性硬化症的驱动因素。这些 CD_4~+CTL渗入纤维化组织，分泌IL-1β和转化生长因子-β，诱导细胞凋亡和过度表达。 活跃的组织重塑。CD163+MerTK+巨噬细胞，通常在凋亡的背景下诱导， 在IgG4-RD损伤中积累，间接表明T细胞诱导的凋亡细胞死亡先于组织 人体自身免疫性纤维化模型的重塑。 这项拟议的ACE计划的努力将得到以下方面的推动：1)组织良好且已经高度- 功能ACE核心；2)MGH转化医学小组，学术临床研究 MGH独有的组织，由ACE基金管理核心组成。

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.