The role of macrophage migration inhibitory factor in autoimmune hepatitis

描述(申请人提供)：自身免疫性肝炎(AIH)是一种慢性疾病，以反复发生的肝细胞损伤、循环自身抗体和自身反应性T细胞为特征。尽管已制定了AIH的诊断指南，但关键的触发因素和免疫途径仍知之甚少。治疗仍然依赖于慢性糖皮质激素，并伴随着许多相关的不良反应。此外，疾病监测是次优的，需要预测性免疫生物标记物将免疫发病机制与临床状态联系起来。巨噬细胞迁移抑制因子(MIF)是一种促炎细胞因子，通过激活关键的先天免疫和获得性免疫通路，介导宿主对感染和应激的反应。MIF的生物活性和MIF基因的多态性与许多自身免疫性疾病有关。将这一点应用到肝病领域，申请人发起了第一个 MIF自身免疫性肝病的研究这份K08提案直接基于 这项研究现已发表在《肝病学》杂志上，该研究假设MIF是一种活跃的 通过与T细胞的相互作用，直接诱导和维持炎性级联反应，从而在AIH中发挥作用。抗MIF治疗和中和MIF受体(CD74)对MIF的调节被认为是保护性的。此外，假设MIF基因多态与疾病严重程度相关，纵向血清MIF和CD74水平可能反映AIH的疾病活动性。因此，本研究的目的是：1)明确MIF在T细胞性肝炎小鼠免疫介导的肝脏炎症信号通路中的作用；2)明确MIF受体CD74释放的细胞机制及其对MIF生物活性的调节作用；3)明确功能性MIF基因多态性、MIF和CD74水平与AIH患者病程的关系。支持数据表明，MIF基因敲除小鼠中缺乏MIF可以保护T细胞肝损伤，小分子MIF抑制剂也具有类似的保护作用。CD74的循环形式抑制MIF的生物活性，并在体外刺激肝细胞释放。最后，在美国和日本的AIH患者中，发现了高危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，K08提案将确定MIF在AIH免疫调节中的关键机制作用，使新的治疗和疾病管理策略成为可能。为了实现这一目标，一个有指导和综合的五年研究和培训战略计划将使申请者能够从实验上检验这些假设，并发展成为致力于翻译肝病的独立研究人员。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博士的关注点。耶鲁大学的协作环境结合了肝脏学和免疫生物学的培训经验，是进行翻译肝病学指导职业发展项目的理想环境。

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.