Transplant Arteriosclerosis: Viral and Host Mechanism

说明(由申请人提供)：本计划的基本目标 在慢性移植排斥反应的免疫发病机制中的作用是解决“TA：病毒和 寄主机制“通过了解这种共同的致病过程 心脏移植受者慢性排斥反应的表现。该计划 该项目的重点是人类巨细胞病毒(HCMV)在 与免疫致病和炎症调节相结合，在 进展为TA的患者。这项研究涉及一个大型的、有组织的多层次 160例心脏移植受者的评价。外周血和 心内膜心肌活检标本将在第一次采集八次 一年，连续三年跟踪免疫学、病毒学和 炎性指标将与TA相关。年的第一个项目 这项计划将集中在巨细胞病毒特异性的CD4和CD8T的贡献 潜伏期或潜伏期再激活过程中的细胞记忆/效应器功能 初次感染的开始和向TA的进展。这个项目将 还要调查细胞的激活状态。负相关是 预计进展为TA的风险和功能性疾病的频率之间 人巨细胞病毒特异性T细胞。该计划的第二个项目将重点放在关卡 人巨细胞病毒DNA的变异和病毒基因表达的诱导 好的。灵敏溶液与DNA原位扩增和杂交 在随访中，将使用方法跟踪病毒dna和mrna水平。 句号。该项目将调查编码或诱导的病毒的作用 趋化因子(UL146/vCXC-L)及其受体(US28)的表达 TA的进展。病毒株的致炎能力和 高度可变的UL146趋化因子基因，从患者进展到TA将是 调查过了。预计年内病毒学指标将有所增加。 晋升为助教。第三个项目将确定硝酸盐的影响 通过重点研究一氧化氮合酶(NOS)途径的两大变化，可以 患者测量：(I)血管超氧阴离子(O2-)增加，以及 (Ii)增加反兴奋剂机构的费用。该项目将调查人巨细胞病毒感染是如何 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。人巨细胞病毒对血管内皮细胞和血管内皮细胞的影响 炎性一氧化氮合酶通路在TA的进展过程中被认为是可能的。重要的是 这三个项目将在外周血液中并行工作 细胞/血浆/血清以及直接在心内膜心肌活检中 采样时间。如此紧张的纵向研究应该会提供最好的 可能的设置，以揭示关联并确定HCMV的贡献 敬助教。药物治疗的机制、预后价值及治疗要点 干预--针对人巨细胞病毒，免疫应答，免疫激活 而免疫致病事件和一氧化氮合酶途径的作用都可能 作为这些合作努力的结果。

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.