Transplant Arteriosclerosis: Viral and Host Mechanism

移植动脉硬化：病毒和宿主机制

• 批准号: 6760866
• 负责人: EDWARD S. Edward S Mocarski
• 金额: $ 134.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-10 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760866
• 关键词: arteriosclerosis; cytomegalovirus; heart transplantation; pathologic process; transplant rejection

DESCRIPTION (provided by applicant): The fundamental objective of this Program in Immunopathogenesis of Chronic Graft Rejection is to address "TA: Viral and Host Mechanisms" by understanding pathogenic processes underlying this common manifestation of chronic rejection in heart transplant recipients. The Program Project focuses on the contribution of human cytomegalovirus (HCMV) in conjunction with immunopathogenic and inflammatory modulation that develops in patients who progress to TA. The study involves a large, organized multi-level evaluation of 160 heart transplant recipients. Peripheral blood and endomyocardial biopsy specimens will be collected eight times over the first year and three times in successive years to follow immune, virologic and inflammatory indicators that will be correlated with TA. The first project in this program will focus on the contribution of the HCMV-specific CD4 and CD8 T cell memory/effector function during the reactivation from latent or the initiation of primary infection and the progression to TA. This project will also investigate the activation state of cells. An inverse correlation is expected between the risk of progression to TA and the frequency of functional HCMV-specific T cells. The second project of this program will focus on levels of HCMV DNA and the induction of viral gene expression in patients at risk of TA. Sensitive solution and in situ DNA amplification and hybridization approaches will be used to follow viral DNA and mRNA levels in the follow-up period. This project will investigate the role of virus encoded or -induced chemokine (UL146/vCXC-l) and chemokine receptor (US28) expression in progression of TA. The proinflammatory capacity of viral strains and the highly variable UL146 chemokine gene, from patients progressing to TA will be investigated. An increase in virological indicators is expected during progression to TA. The third project will determine the impact of the Nitric Oxide Synthase(NOS) pathway by focusing on two major changes that can be measured in patients: (i) increases in vascular superoxide anion (O2-), and (ii) increases in ADMA. This project will investigate how HCMV infection augments these abnormalities via cytokine induced alterations in oxidative stress and ADMA accumulation. An impact of HCMV on endothelial and inflammatory NOS pathways is expected during progression to TA. Importantly, all three projects will work in parallel in peripheral blood cells/plasma/serum as well as directly in endomyocardial biopsies at all sampling times. Such an intense longitudinal study should provide the best possible setting to uncover associations and identify the contribution of HCMV to TA. The mechanisms, prognostic value and points of therapeutic intervention-directed at HCMV, the immune response to HCMV, immune activation and immunopathogenic events and the role of NOS pathways will all potentially emerge as a result of these collaborative efforts.

描述（由申请人提供）：该计划的基本目标 在慢性移植排斥反应的免疫发病中是为了解决“ TA：病毒和 宿主机制“通过理解这种常见的病原过程 心脏移植受者慢性排斥的表现。该程序 项目侧重于人类巨细胞病毒（HCMV）在 与免疫发育和炎症调节的结合 发展为TA的患者。该研究涉及一个大型的多层次 评估160名心脏移植受者。外周血和 心内膜活检标本将在第一次收集八次 连续几年和三次遵循免疫，病毒学和 将与TA相关的炎症指标。第一个项目 该程序将重点介绍HCMV特异性CD4和CD8 T的贡献 从潜在或从潜在或 初次感染和向TA的进展。这个项目将 还研究细胞的激活状态。相关性是 预期发展到TA的风险与功能频率 HCMV特异性T细胞。该计划的第二个项目将重点放在级别上 HCMV DNA和患者的病毒基因表达的诱导风险 ta。敏感溶液和原位DNA扩增和杂交 方法将在随访中遵循病毒DNA和mRNA水平 时期。该项目将调查编码或引起的病毒的作用 趋化因（UL146/VCXC-L）和趋化因子受体（US28）表达 ta的进展。病毒株和 从发展到TA的患者的高度可变的UL146趋化因子基因将是 调查。预计在病毒学指标会增加 进展到ta。第三个项目将确定一氮的影响 氧化物合酶（NOS）途径通过重点关注两个可以是的主要变化 在患者中测量：（i）增加血管超氧阴离子（O2-）和 （ii）ADMA增加。该项目将调查HCMV感染如何 通过细胞因子诱导的氧化改变来增强这些异常 压力和ADMA积累。 HCMV对内皮和 预计在进展过程中，预计炎症的NOS途径。重要的是， 这三个项目将与外围血液并联起作用 细胞/血浆/血清以及直接在内膜活检中 采样时间。如此激烈的纵向研究应该提供最好的 可能的设置以发现关联并确定HCMV的贡献 到ta。机制，预后价值和治疗点 干预措施在HCMV时指导，对HCMV的免疫反应，免疫激活 免疫发病事件以及NOS途径的作用都可能有可能 由于这些协作的努力而出现。