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: 10611978
• 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/10611978
• 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; Clonal Expansion; Collection; Color; Cytotoxic T-Lymphocytes; Data; Disease; Dose; Endothelial Cells; Event; FOXP3 gene; Fibroblasts; Fibrosis; Flare; Functional disorder; Funding; General Hospitals; Human; IL17 gene; IgG4; In Situ; Inflammation; Inflammatory; Interleukin 6 Receptor; Interleukin-1 beta; Laboratories; Lesion; Link; Lymphocyte Subset; Macrophage; 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; Risk Assessment; Role; Safety; Sampling; Scientist; Site; Smooth Muscle Myocytes; Systemic Scleroderma; T cell differentiation; T cell infiltration; 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; biomarker discovery; biomarker performance; cohort; design; efficacy evaluation; health related quality of life; human model; human monoclonal antibodies; humanized monoclonal antibodies; innovation; instrument; interest; novel; novel therapeutics; open label; peripheral blood; programs; prospective; safety assessment; serological marker; 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.

转译研究的力量已由麻省总医院举例说明

项目成果

Granulomatous uveitis secondary to IgG4-related disease.

继发于IgG4相关疾病的肉芽肿性葡萄膜炎。

• DOI: 10.1093/rap/rkab084
• 发表时间: 2021
• 期刊: Rheumatology advances in practice
• 影响因子: 3.1
• 作者: Katz G;Harvey L;Stone JH
• 通讯作者: Stone JH

Pulmonary and coronary arterial abnormalities in patients with IgG4-related disease.

• DOI: 10.1016/j.radcr.2022.09.070
• 发表时间: 2022-12
• 期刊: Radiology case reports
• 作者: Cochran RL;Brideau HR;Wu MY;Stone JH;Wallace ZS;Little BP
• 通讯作者: Little BP

The Role of Quantification of Glucocorticoid-associated Toxicity in Severe Asthma.

• DOI: 10.33696/immunology.3.074
• 发表时间: 2021
• 期刊: Journal of cellular immunology
• 作者: McDowell PJ;Stone JH;Heaney LG
• 通讯作者: Heaney LG

Treatment failure in giant cell arteritis.

• DOI: 10.1136/annrheumdis-2021-220347
• 发表时间: 2021-11
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4
• 作者: Unizony SH;Bao M;Han J;Luder Y;Pavlov A;Stone JH
• 通讯作者: Stone JH