IMMUNOMODULATION OF RETROVIRAL CARDIOPATHOLOGY

逆转录病毒心脏病学的免疫调节

• 批准号: 6184164
• 负责人: RONALD Ross WATSON
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184164
• 关键词: HIV infections; Retroviridae disease; T cell receptor; cell adhesion molecules; cellular pathology; cytotoxicity; disease /disorder model; histopathology; immunoregulation; interferon gamma; interleukin 4; intravital microscopy; laboratory mouse; myocardium disorder; nitric oxide synthase; nuclear factor kappa beta; oxidative stress; tocopherols

DESCRIPTION (Adapted from applicant's abstract) Pericardial effusion, cardiomyopathy, and left ventricular dysfunction are prevalent in patients with AIDS. The applicants' model of murine retrovirus infection mimics much of the immune dysfunction and cardiac toxicity found during HIV infection. They expect that cytokine dysregulation and increased oxidative stress in the mouse heart due to murine retrovirus infection will increase the formation of NfkB expression resulting in of ICAM-1 and T-helper cell hyperactivtion and secretion of cytokines. This cascade will stimulate PMN and endothelial cell activation and promote the formation of iNOS, resulting in cardiac muscle and endothelial cell damage and ventricular dysfunction. They will perform molecular analysis of NfkB translocation to the nucleus. They will measure simultaneously the resulting RNA message and proteins for iNOS or ICAM-1 in heart tissues. The left ventricular function will be quantitated in vivo with pressure volume loop to define the ventricular dysfunction and characterize the therapeutic effect of immunomodulators. They propose to examine the PMN-mediated tissue injury hypothesis in the heart and coronary vasculative. They will investigate PMN sequestration and activation in the heart and test for oxidative damage. They will correlate the retroviral progression to the coronary microvascular injury through intravital microscopy, PMN accumulation and PMN function. They will limit the deleterious cardiac effects during retrovial infection by preventing dysfunctional cytokine production, slowing the resulting immune dysregulation and increased oxidative damage. They will examine the efficacy of their proven methods that prevented much of the cytokine dysregulation and oxidative damage to the heart: T-cell receptor Vbeta 8.1 injection, vitamin E supplementation, and interferon-gamma or anti IL-4 antisera injection. They will also accentuate cytokine dysregulation by IL-4 injection to accelerate immune dysfunction and cardiopathology. These model studies will increase understanding of retrovirus induced immune dysfunction and its role in cardiac pathology. The treatments that found to prevent cytokine dysregulation and cardiotoxicitiy in retrovirally infected mice will then be applicable to reducing heart disease in HIV infected patients (End of Abstract)

描述 （改编自申请人摘要）心包积液、心肌病、 艾滋病患者普遍存在左心室功能障碍。 的 本申请人的鼠逆转录病毒感染模型模拟了大部分免疫反应， 在HIV感染期间发现的功能障碍和心脏毒性。 他们预计 小鼠体内细胞因子失调和氧化应激增加 心脏由于鼠逆转录病毒感染会增加NfkB的形成 表达导致ICAM-1和T辅助细胞过度活化， 细胞因子的分泌。 这种级联反应将刺激PMN和内皮细胞 细胞活化，促进iNOS的形成，导致心脏 肌肉和内皮细胞损伤以及心室功能障碍。 他们将 进行NfkB易位到细胞核的分子分析。 他们将 同时测量所产生的RNA信息和蛋白质的iNOS或 心肌组织中ICAM-1的表达。 将定量左心室功能 在体内使用压力容积环来定义心室功能障碍， 描述免疫调节剂的治疗效果。 他们提议 检查心脏和冠状动脉中PMN介导的组织损伤假说 血管的 他们将研究中性粒细胞的隔离和激活， 心脏和氧化损伤测试 他们会将逆转录病毒 冠状动脉微血管损伤的进展 显微镜检查，PMN积聚和PMN功能。 他们就会限制 通过预防逆转录病毒感染对心脏的有害影响 细胞因子的产生功能失调， 失调和氧化损伤增加。 他们将研究 他们证明了他们的方法的有效性， 调节失调和心脏氧化损伤：T细胞受体Vbeta 8.1 注射，维生素E补充，干扰素-γ或抗IL-4 抗血清注射。 它们还将通过以下方式加重细胞因子失调： IL-4注射加速免疫功能障碍和心脏病理学。 这些 模型研究将增加对逆转录病毒诱导免疫的理解， 功能障碍及其在心脏病理学中的作用。 这些治疗方法 预防逆转录病毒感染的细胞因子失调和心脏毒性 小鼠将适用于减少艾滋病毒感染者的心脏病 患者（摘要结束）