MIF inhibition as a novel treatment for autoimmune myocarditis

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，并且经常进展为扩张型心肌病，占心力衰竭病例的1/25;然而，对于这种破坏性疾病没有特异性和有效的治疗方法。强有力的证据支持急性（例如病毒性）心肌炎进展为慢性心肌炎和随后的扩张型心肌病最常由针对心脏组织的自身免疫攻击介导;然而，由于未知原因，免疫抑制治疗不是非常有效，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，我们发现免疫抑制性糖皮质激素（GC）治疗巨噬细胞移动抑制因子（MIF）基因敲除小鼠完全阻止了实验性自身免疫性心肌炎（EAM），心肌炎的动物模型，扩张型心肌病（DCM）的进展。因此，我们将在本申请中测试MIF抑制剂与GC治疗的组合作为该疾病的新治疗方法。这些研究的理由是，MIF已被证明可以促进EAM。此外，MIF刺激致病性T细胞产生IL-17，这是诱导EAM的关键细胞因子。重要的是，MIF是独特的，因为它是唯一已知的由GC诱导的促炎细胞因子，并且随后反调节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关键作用，并且在心肌炎患者中抑制这种细胞因子与GC结合可能代表一种新的治疗方法和主要的治疗进展。我们将测试我们的中心假设与以下具体目标：目标1。确定MIF抑制剂在预防EAM患者对GC治疗耐药和扩张型心肌病进展方面的疗效。我们将检验用抗MIF mAb或小分子MIF抑制剂抑制MIF将预防Dex处理的BALB/c野生型（wt）小鼠中类似于MIF-/-小鼠的DCM的假设。目标2.确定MIF如何促进EAM对Dex的耐药性和进展为DCM的关键机制。我们将检验以下假设：MIF通过调节趋化因子/趋化因子受体和归巢分子，引导炎性细胞和Prominin-1/CD 133+髓样前体细胞向心脏募集并分化为成纤维细胞和DCM，从而抑制EAM中GC治疗效果和DCM进展。我们期望这些研究将提供目前尚无法获得的重要信息，并对心肌炎和扩张型心肌病的研究和治疗产生重大而持久的影响。

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.