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(申请人提供)：心肌炎是导致高达20%的年轻人猝死的重要原因，并经常进展为扩张型心肌病，占心力衰竭病例的四分之一；然而，对于这种毁灭性的疾病，还没有特效的治疗方法。强有力的证据支持，急性(如病毒性)心肌炎的进展和随后的扩张型心肌病最常见的是由对心脏组织的自身免疫攻击所介导的；然而，由于未知的原因，免疫抑制治疗并不是非常有效，目前的治疗重点是控制临床症状和提供支持性护理。在我们的初步研究中，我们发现巨噬细胞移动抑制因子(MIF)基因敲除小鼠的免疫抑制糖皮质激素(GC)激素治疗完全阻止了实验性自身免疫性心肌炎(EAM)(一种心肌炎的动物模型)向扩张型心肌病(DCM)的进展。因此，我们将在目前的应用中测试MIF抑制剂联合GC治疗作为治疗该疾病的新方法。这些研究的合理性在于，MIF已被证明能促进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是独一无二的，它是唯一已知的由GCs诱导的致炎细胞因子，并随后反向调节GC介导的免疫抑制。由于地塞米松(Dex)对MIF基因敲除(MIF-/-)小鼠的治疗完全阻止了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发挥关键作用，并且在心肌炎患者中抑制这一细胞因子与GC联合可能代表一种新的治疗方法和重大治疗进展。我们将通过以下具体目标来验证我们的中心假说：目的1.确定MIF抑制剂在预防EAM对GC治疗的耐药性和进展为扩张型心肌病方面的有效性。我们将验证这样一种假设，即用抗MIF单抗或小分子MIF抑制剂抑制MIF将防止地塞米松处理的BALB/c野生型(Wt)小鼠发生DCM，这一假设类似于MIF-/-小鼠。目的2.探讨巨噬细胞集落刺激因子(MIF)促进EAM对地塞米松(Dex)耐药并进展为DCM的关键机制(S)。我们将验证MIF通过调节趋化因子/趋化因子受体和归巢分子，引导炎症细胞和Prominin-1/CD133+髓系前体细胞向心脏募集，并向成纤维细胞和DCM分化，从而抑制EAM的GC治疗效果和进展为DCM的假说。我们预计，拟议的研究将提供目前无法获得的重要信息，这些信息将对心肌炎和扩张性心肌炎的研究和治疗产生重大和持久的影响。