MIF inhibition as a novel treatment for autoimmune myocarditis

MIF 抑制作为自身免疫性心肌炎的新型治疗方法

• 批准号: 8793098
• 负责人: THOMAS G. FORSTHUBER
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793098
• 关键词: Accounting; Acute; Adoptive Transfer; Affect; Animal Model; Animals; Autoantibodies; Autoimmune Process; Biological Assay; Cardiac; Cardiac Myosins; Cells; Chronic; Clinical; Confocal Microscopy; Development; Dexamethasone; Dilated Cardiomyopathy; Disease; Employee Strikes; Enzyme-Linked Immunosorbent Assay; Evaluation; Fibroblasts; Fibrosis; Flow Cytometry; Glucocorticoids; Health; Heart; Heart failure; Hematoxylin and Eosin Staining Method; Histopathology; Homing; Hormones; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Immunosuppression; Immunosuppressive Agents; Inbred BALB C Mice; Inflammatory; Inflammatory Infiltrate; Interferon Type II; Interleukin-17; Knock-out; Knockout Mice; Mediating; Medical; Migration Inhibitory Factor; Mining; Modeling; Monoclonal Antibodies; Mus; Myelogenous; Myocarditis; Myosin Heavy Chains; Outcome; Patients; Peptides; Play; Production; Research; Resistance; Role; Serum; Severities; Staining method; Stains; Sudden Death; Supportive care; Symptoms; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Trichrome stain method; Viral; Wild Type Mouse; assault; base; cell motility; chemokine; chemokine receptor; clinical efficacy; cytokine; effective therapy; enzyme linked immunospot assay; expectation; inhibitor/antagonist; novel; novel therapeutic intervention; novel therapeutics; phenylpyruvate tautomerase; pre-clinical; precursor cell; prevent; prominin; small molecule; treatment effect; treatment strategy; young adult

DESCRIPTION (provided by applicant): Myocarditis is an important cause of sudden death in up to 20% of young adults and frequently progresses to dilated cardiomyopathy, which accounts for up to 1 in 25 cases of heart failure; yet, there is no specific and effective treatment for thi devastating condition. Strong evidence supports that progression of acute (e.g. viral) myocarditis to chronic myocarditis and ensuing dilated cardiomyopathy are most frequently mediated by an autoimmune assault against heart tissue; however, for unknown reasons immunosuppressive treatments are not very effective and current treatment focuses on managing clinical symptoms and providing supportive care. In our preliminary studies we found that immunosuppressive glucocorticoid (GC) hormone treatment of macrophage migration inhibitory factor (MIF) knockout mice completely prevented the progression of experimental autoimmune myocarditis (EAM), an animal model of myocarditis, to dilated cardiomyopathy (DCM). Therefore, we will test in the present application inhibitors of MIF in combination with GC treatment as novel therapeutic approach for this disease. The rational for these studies is that MIF has been shown to promote EAM. Furthermore, MIF stimulates IL-17 production by pathogenic T cells, which is a critical cytokine for induction of EAM. Importantly, MIF is unique i that it is the only known proinflammatory cytokine induced by GCs and to subsequently counter-regulate GC- mediated immunosuppression. Since treatment of MIF knockout (MIF-/-) mice with Dexamethasone (Dex) completely prevented progression of EAM to DCM (our preliminary results), we hypothesize that MIF plays a critical role in resistance to immunosuppressive treatment and that inhibiting this cytokine in combination with GCs in myocarditis patients could represent a novel treatment approach and major therapeutic advance. We will test our central hypothesis with the following specific aims: Aim 1. To determine the efficacy of MIF inhibitors in preventing resistance to GC treatment in EAM and progression to dilated cardiomyopathy. We will test the hypothesis that inhibition of MIF with anti-MIF mAb or small molecule MIF inhibitors will prevent DCM in Dex treated BALB/c wild-type (wt) mice analogous to MIF-/- mice. Aim 2. To determine the key mechanism(s) how MIF promotes resistance to Dex in EAM and progression to DCM. We will test the hypothesis that MIF inhibits GC treatment effects in EAM and progression to DCM by modulating chemokines/chemokine receptors and homing molecules guiding recruitment of inflammatory cells and Prominin-1/CD133+ myeloid precursor cells to the heart and their differentiation into fibroblasts and DCM. We expect that the proposed studies will provide important information that is currently not available and which will have significant and lasting impact on research and treatment of myocarditis and DCM.

描述（由申请人提供）：心肌炎是高达20%的年轻人猝死的重要原因，并且经常发展为扩张性心肌病，占心力衰竭病例的1 / 25；然而，对于这种毁灭性的疾病，目前还没有具体有效的治疗方法。强有力的证据支持急性（如病毒性）心肌炎进展为慢性心肌炎和随后的扩张性心肌病最常由自身免疫攻击心脏组织介导；然而，由于未知的原因，免疫抑制治疗不是很有效，目前的治疗侧重于控制临床症状和提供支持性护理。在我们的初步研究中，我们发现免疫抑制糖皮质激素（GC）激素治疗巨噬细胞迁移抑制因子（MIF）敲除小鼠完全阻止实验性自身免疫性心肌炎（EAM），一种心肌炎动物模型，向扩张型心肌病（DCM）发展。因此，我们将在目前的应用中测试MIF抑制剂联合GC治疗作为这种疾病的新治疗方法。这些研究的理由是MIF已被证明可以促进EAM。此外，MIF刺激致病T细胞产生IL-17，这是诱导EAM的关键细胞因子。重要的是，MIF的独特之处在于它是唯一已知的由GC诱导的促炎细胞因子，并随后拮抗GC介导的免疫抑制。由于用地塞米松（Dex）治疗MIF敲除（MIF-/-）小鼠完全阻止了EAM向DCM的进展（我们的初步结果），我们假设MIF在免疫抑制治疗的抵抗中起着关键作用，并且在心肌炎患者中抑制这种细胞因子与GCs联合可能代表一种新的治疗方法和重大的治疗进展。我们将用以下具体目标来检验我们的中心假设：目标1。确定MIF抑制剂在预防EAM患者对GC治疗的耐药和向扩张型心肌病发展方面的疗效。我们将验证一种假设，即用抗MIF单抗或小分子MIF抑制剂抑制MIF，可以防止Dex处理的BALB/c野生型（wt）小鼠（类似于MIF-/-小鼠）的DCM。目标2。确定MIF如何促进EAM对Dex的耐药性并进展为DCM的关键机制。我们将通过调节趋化因子/趋化因子受体和引导炎症细胞和pronin -1/CD133+髓样前体细胞向心脏募集并向成纤维细胞和DCM分化的归巢分子来验证MIF抑制GC治疗EAM和DCM进展的假设。我们期望所提出的研究将提供目前尚未获得的重要信息，并将对心肌炎和DCM的研究和治疗产生重大而持久的影响。