Defining the Pathogenic Contribution of High Genotypic MIF Expression

定义高基因型 MIF 表达的致病贡献

• 批准号: 10402761
• 负责人: RICHARD J BUCALA
• 金额: $ 36.48万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402761
• 关键词: Adoptive Transfer; Alleles; Apoptosis; Arthritis; Autoimmune Diseases; Binding; Biological Response Modifier Therapy; Blood; CD44 gene; Cardiovascular Diseases; Cell Culture Techniques; Cells; Chronic Childhood Arthritis; Clinical; Collagen; Data; Disease; Disease Progression; Evaluation; Exons; Experimental Arthritis; Fc Receptor; Fibroblasts; Genes; Genetic; Genetic Polymorphism; Genotype; Glucocorticoids; Human; Immunology; Inflammation; Inflammatory; Inflammatory Arthritis; Joints; Laboratories; Longevity; Mediating; Memory; Microsatellite Repeats; Migration Inhibitory Factor; Morbidity - disease rate; Mouse Strains; Mus; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Production; Protein Isoforms; RNA Splicing; Recurrent disease; Refractory; Relapse; Rheumatoid Arthritis; Role; Scleroderma; Signal Transduction; Site; Symptoms; Synovial Fluid; Synovial Membrane; Synovial joint; Synovitis; Systemic Lupus Erythematosus; T cell response; T memory cell; T-Lymphocyte; Testing; Tissues; United States; Variant; Vasculitis; Work; arthropathies; base; cytokine; effective therapy; experience; experimental study; human migration; immunopathology; inhibitor; insight; joint destruction; macrophage; mouse model; novel; peripheral blood; programs; promoter; receptor; research clinical testing; response; risk variant; tool; trafficking; transcription factor; translational impact; treatment response

PROJECT SUMMARY Rheumatoid arthritis (RA) remains incurable despite biologic therapies. We previously identified a functional promoter polymorphism in the gene for macrophage migration inhibitory factor (MIF) - a cytokine our group first cloned, that is associated with erosive joint destruction in RA. MIF is known to regulate the innate response by inhibiting glucocorticoid action, suppressing activation-induced apoptosis, and promoting macrophage retention in tissues. The role of MIF and high expression MIF alleles is not fully understood however, especially with respect to alterations in the adaptive response that perpetuate inflammation, pathologic progression, and disease persistence. We have discovered a novel T cell subpopulation that expresses the MIF receptor (CD74), expands during arthritis, and recapitulates disease when transferred into naïve hosts. A similar population exists in human rheumatoid synovium. We hypothesize that CD4+CD74+ T cells play a key role in rheumatoid inflammation, disease progression, and relapse. We will pursue three Specific Aims in this proposal: 1. Define the pathogenic role of a novel, MIF receptor expressing T cell sub-population (CD4+CD74+ T cells) in inflammatory arthritis. We hypothesize that CD4+CD74+ T cells express inflammatory cytokines and chemotactic receptors that contribute to synovial joint destruction. We will characterize the MIF signaling and effector responses of mouse and human CD4+CD74+ T cells, identify trafficking factors/receptors, and establish their pathogenic potential. 2. Define the impact of high-genotypic MIF expression on joint immunopathology in a novel humanized MIF mouse model. We hypothesize that MIF expression drives pathologic CD4+CD74+ T cell trafficking and effector responses, and unremitting arthritis. We will test this hypothesis using novel humanized MIF mice that express low-expression and high-expression human MIF alleles. 3. Evaluate the impact of ICBP90 inhibition on MIF expression in humanized MIF mice and in high genotypic MIF expressing human cells. We identified both the transcription factor (ICBP90) that upregulates MIF transcription at its variant promoter microsatellite (-794 CATT5-8), and a drug-like molecule (CMFT) that blocks ICBP90 binding to this promoter site. We hypothesize that ICBP90 inhibition will ameliorate the MIF- dependent expansion and effector response of CD4+CD74+ T cells. We will test this possibility in experimental arthritis and examine ICBP90 inhibition in high-genotypic MIF expressing human cells obtained from peripheral blood and from rheumatoid synovial tissue. The completion of these Aims will provide insight into the pathologic role of a novel, MIF receptor expressing T cell population and the contribution of MIF risk alleles to rheumatoid inflammation. These studies also will accelerate consideration of a precision-based approach for treating RA joint destruction.

项目摘要 风湿性关节炎（RA）仍然无法治愈，尽管生物疗法。我们之前发现了一个 巨噬细胞移动抑制因子基因功能启动子多态性 本课题组首次克隆了与类风湿关节炎关节破坏有关的基因。众所周知，MIF调节 通过抑制糖皮质激素作用，抑制活化诱导的细胞凋亡， 促进巨噬细胞滞留在组织中。MIF及其高表达等位基因的作用尚不完全 然而，理解，特别是在适应性反应的改变， 炎症、病理进展和疾病持续性。我们发现了一种新的T细胞 表达MIF受体（CD 74）的亚群，在关节炎期间扩增，并重现疾病 当转移到幼稚宿主体内时在人类类风湿性滑膜中也存在类似的群体。我们 假设CD 4 + CD 74 + T细胞在类风湿性炎症、疾病进展和 复发我们将在这项建议中追求三个具体目标：1。定义小说的致病作用， 炎症性关节炎中表达MIF受体的T细胞亚群（CD 4 + CD 74 + T细胞）。我们 假设CD 4 + CD 74 + T细胞表达炎性细胞因子和趋化性受体， 导致滑膜关节破坏。我们将描述的MIF信号和效应器的反应， 小鼠和人CD 4 + CD 74 + T细胞，鉴定运输因子/受体，并确定其致病性 潜力2.明确高基因型MIF表达对关节免疫病理学的影响， 新型人源化MIF小鼠模型。我们假设MIF表达驱动病理性CD 4 + CD 74 + T细胞运输和效应反应与持续性关节炎。我们将使用新的方法来验证这一假设。 人源化MIF小鼠，其表达低表达和高表达人MIF等位基因。3.评价 ICBP 90抑制对人源化MIF小鼠和高基因型MIF中MIF表达影响 表达人类细胞。我们鉴定了上调MIF的转录因子（ICBP 90）和 在其变体启动子微卫星（-794 CATT 5 -8）处转录，以及一种药物样分子（CMFT）， 阻断ICBP 90与该启动子位点的结合。我们假设ICBP 90抑制将改善MIF- CD 4 + CD 74 + T细胞的依赖性扩增和效应子应答。我们将测试这种可能性， 实验性关节炎，并在表达高基因型MIF的人细胞中检测ICBP 90抑制 从外周血和类风湿性滑膜组织中获得。这些目标的完成将 提供了一种新的，表达MIF受体的T细胞群的病理作用的见解， MIF风险等位基因对类风湿性炎症的贡献。这些研究也将加速考虑 治疗RA关节破坏的精确方法。