The role of macrophage migration inhibitory factor in autoimmune hepatitis

巨噬细胞迁移抑制因子在自身免疫性肝炎中的作用

• 批准号: 8822069
• 负责人: David Assis
• 金额: $ 15.29万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822069
• 关键词: Acute; Adverse effects; Alleles; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmune Process; Biological Markers; Blood Tests; Blood specimen; Bone Marrow; Cell membrane; Cells; Chimeric Proteins; Chronic; Chronic Disease; Clinical; Concanavalin A; Cytokine Signaling; Data; Diagnosis; Disease; Disease Management; Disease Marker; Disease Progression; Disease remission; Dose; Effectiveness; Enzymes; Etiology; Fellowship; Frequencies; Genetic Polymorphism; Genotype; Glucocorticoids; Guidelines; Hepatic; Hepatic Stellate Cell; Hepatitis; Hepatocyte; Hepatology; Human; Immigration; Immune; Immune response; Immune system; Immunobiology; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Interferon Type II; Interferons; Investigation; Japan; Knock-out; Knockout Mice; Kupffer Cells; Life; Link; Linkage Disequilibrium; Liver; Liver diseases; Lupus Nephritis; Measures; Mediating; Medical Genetics; Membrane; Mentors; Meta-Analysis; Microsatellite Repeats; Migration Inhibitory Factor; Modeling; Monitor; Mus; Neuroendocrine Cell; Pathologic; Pathway interactions; Patients; Pattern; Phase; Phenotype; Play; Population; Prednisone; Primary biliary cirrhosis; Proteins; Proteolysis; Publishing; Recombinants; Recurrence; Recurrent disease; Regulation; Research; Research Personnel; Research Training; Rheumatoid Arthritis; Risk; Role; Serum; Severities; Severity of illness; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Stimulus; Strategic Planning; Stress; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic Effect; Time; Tissues; Toxic effect; Training; Ulcerative Colitis; Universities; Work; base; career development; collaborative environment; cytokine; experience; genetic variant; high risk; immunopathology; immunoregulation; in vivo; inhibitor/antagonist; liver inflammation; liver injury; macrophage; mouse model; novel; peripheral blood; phenylpyruvate tautomerase; pleiotropism; presenilin-1; promoter; public health relevance; receptor; research study; response; small molecule

DESCRIPTION (provided by applicant): Autoimmune hepatitis (AIH) is a chronic disease characterized by recurrent hepatocellular injury, circulating autoantibodies, and autoreactiv T-cells. Despite established guidelines for the diagnosis of AIH, key triggers and immunologic pathways are poorly understood. Therapy remains dependent on chronic glucocorticoids with numerous associated adverse effects. Further, disease monitoring is sub-optimal and there is a need for predictive immune biomarkers to link immunopathogenesis to the clinical status. Macrophage Migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine that mediates the host response to infection and stress by activating key innate and adaptive immune pathways. MIF's bioactivity and MIF polymorphisms have been implicated in many autoimmune disorders. Applying this to the field of hepatology, the applicant initiated the first investigation of MIF autoimmune liver diseases. This K08 proposal is directly based on that work, now published in Hepatology, under the hypothesis that MIF plays an active role in AIH by directly inducing and sustaining the inflammatory cascade through interactions with T-cells. Anti-MIF therapy and MIF modulation by a neutralizing MIF receptor (CD74) are hypothesized to be protective. Further, MIF polymorphisms are hypothesized to correlate with disease severity, and longitudinal serum MIF and CD74 levels may reflect AIH disease activity. Accordingly, the aims of this proposal are to: 1) Define the rol of MIF in signaling pathways of immune-mediated liver inflammation in a mouse model of T-cell hepatitis~ 2) Define the cellular mechanisms responsible for release of the MIF receptor CD74 and its modulating effect on MIF bioactivity~ and 3) Define the relationship of functional MIF genetic polymorphisms, and MIF and CD74 serum levels, to the disease course in AIH patients. Supporting data indicates that MIF absence in knockout mice protects against T-cell liver injury, and that a small-molecule MIF inhibitor is similarly protective. The circulating formof CD74 inhibits MIF bioactivity and is released from hepatic cells following stimulation i vitro. Finally, a genetic-clinical relationship between a high-risk MIF allele (-173*C) nd increase in both serum ALT and prednisone requirements was found in AIH patients from the US and from Japan. Based on these results, the K08 proposal will define a key mechanistic role for MIF in the immunoregulation of AIH, enabling new strategies for therapy and disease management. To accomplish this, a mentored and integrated five-year strategic plan for research and training will enable the applicant to experimentally test these hypotheses and to develop into an independent investigator devoted to translational hepatology. The application of MIF to AIH is novel and independent from the focus of both co-mentors, Drs. James Boyer and Richard Bucala. The collaborative environment at Yale University, combining training experience in hepatology and immunobiology, represents an ideal setting in which to conduct this mentored career development project in translational hepatology.

描述（由申请人提供）：自身免疫性肝炎（AIH）是一种慢性疾病，其特征为复发性肝细胞损伤、循环自身抗体和自身反应性T细胞。尽管AIH的诊断指南已经建立，但对关键的触发因素和免疫途径知之甚少。 治疗仍然依赖于慢性糖皮质激素与许多相关的不良反应。此外，疾病监测是次优的，并且需要预测性免疫生物标志物来将免疫发病机制与临床状态联系起来。 巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子，其通过激活关键的先天性和适应性免疫途径来介导宿主对感染和应激的反应。MIF的生物活性和MIF多态性与许多自身免疫性疾病有关。将其应用于肝病学领域，申请人发起了第一个 MIF自身免疫性肝病的研究 本K 08提案直接基于 这项工作，现在发表在肝病学，假设MIF发挥积极的作用， 通过与T细胞的相互作用直接诱导和维持炎症级联反应，在AIH中发挥作用。 假设抗MIF治疗和通过中和MIF受体（CD 74）调节MIF是保护性的。 此外，假设MIF多态性与疾病严重程度相关，纵向血清MIF和CD 74水平可能反映AIH疾病活动性。因此，本提案的目的是：1）确定MIF在T细胞肝炎小鼠模型中免疫介导的肝脏炎症的信号传导途径中的作用~ 2）确定负责释放MIF受体CD 74的细胞机制及其对MIF生物活性的调节作用~和3）确定功能性MIF遗传多态性的关系，MIF、CD 74水平与AIH患者病程的关系。支持性数据表明，在基因敲除小鼠中缺乏MIF可以保护T细胞肝损伤，并且小分子MIF抑制剂具有类似的保护作用。循环形式的CD 74抑制MIF的生物活性，并在体外刺激后从肝细胞释放。 最后，在美国和日本的AIH患者中发现了高风险MIF等位基因（-173*C）与血清ALT和泼尼松需求增加之间的遗传-临床关系。 基于这些结果，K 08提案将确定MIF在AIH免疫调节中的关键机制作用，从而实现治疗和疾病管理的新策略。为了实现这一目标，一个指导和综合的五年研究和培训战略计划将使申请人能够通过实验测试这些假设，并发展成为一个独立的研究者致力于转化肝病学。 MIF在AIH中的应用是新颖的，独立于两位共同导师James Boyer博士和Richard Bucala博士的关注。 耶鲁大学的合作环境，结合了肝病学和免疫生物学的培训经验，代表了一个理想的环境，可以在转化肝病学中进行这个指导性的职业发展项目。