The role of Interleukin-3 in autoimmune myocarditis

Interleukin-3在自身免疫性心肌炎中的作用

• 批准号: 420580046
• 负责人: Dr. Henrike Janssen
• 金额: --
• 依托单位: Klinik für Anästhesiologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/420580046?language=en
• 关键词: role; Interleukin; autoimmune; myocarditis

Myocarditis is the leading cause of heart failure predominantly in males under the age of 40. The majority of cases are based on infections, dominated by Coxsackievirus B3 in Europe and North America. Although half of infections will resolve within 4 weeks, up to 30% of patients will reach a chronic stage, ending in dilated cardiomyopathy (DCM). Diagnosis is difficult, with endomyocardial biopsy being considered the gold standard. Where no viral genome, but histopathological signs of myocarditis can be detected, diagnosis of autoimmune myocarditis needs to be taken into account. For all subtypes of myocarditis, therapy includes symptom control of arrhythmias and heart failure. Potential immunomodulatory, as well immunosuppressive therapies are investigated. However, with incomplete understanding of the pathomechanism these lack specificity. There is evidence that autoimmune myocarditis is mediated by T cells. After viral infection and potential resolution, autoimmunity develops because the virus shares epitopes with cardiac proteins, and because infection may cause damage to cardiomyocytes, exposing autoantigens. The role of interleukin-3, and its potential impact on a T cell mediated inflammatory cascade in myocarditis, has not been elucidated. Preliminary data by the host lab states that interleukin-3 knockout mice show less myocardial inflammation, specifically less influx of leukocytes, and less myocardial damage than the referring wildtype in a model of myocarditis. Patients suffering myocarditis have more expression of interleukin-3 in the myocardium, suggesting a crucial role in humans as well. In the proposed project, I will investigate how the absence of interleukin-3 impacts upon the inflammatory profile of leukocytes in a murine model of autoimmune myocarditis. I will explore the source of interleukin-3 by organ and cell type and, finally, examine the impact of a systemic interleukin-3 block as a potential target for immunomodulatory therapy. The insights from this project may lead to new treatment strategies for myocarditis.

心肌炎是心力衰竭的主要原因，主要发生在40岁以下的男性中。大多数病例是基于感染，在欧洲和北美以柯萨奇病毒B3为主。虽然一半的感染将在4周内消退，但高达30%的患者将达到慢性阶段，最终导致扩张型心肌病（DCM）。诊断困难，肌内膜活检被认为是金标准。如果没有病毒基因组，但可以检测到心肌炎的组织病理学体征，则需要考虑自身免疫性心肌炎的诊断。对于心肌炎的所有亚型，治疗包括心律失常和心力衰竭的症状控制。研究了潜在的免疫调节和免疫抑制疗法。然而，由于对病理机制的不完全理解，这些缺乏特异性。有证据表明，自身免疫性心肌炎是由T细胞介导的。病毒感染和潜在解决后，自身免疫会发展，因为病毒与心脏蛋白共享表位，并且感染可能会对心肌细胞造成损害，暴露自身抗原。白细胞介素-3的作用及其对心肌炎中T细胞介导的炎症级联反应的潜在影响尚未阐明。宿主实验室的初步数据表明，在心肌炎模型中，白细胞介素-3敲除小鼠的心肌炎症较少，特别是白细胞流入较少，心肌损伤也比参照野生型小鼠少。患有心肌炎的患者在心肌中有更多的白细胞介素-3表达，这表明在人类中也起着至关重要的作用。在这个项目中，我将研究白细胞介素-3的缺乏如何影响自身免疫性心肌炎小鼠模型中白细胞的炎症特征。我将通过器官和细胞类型探讨白细胞介素-3的来源，最后，研究全身性白细胞介素-3阻断作为免疫调节治疗的潜在靶点的影响。该项目的见解可能会导致心肌炎的新治疗策略。