MODULATING LYMPHOTOXINS IN PRIMATES FOR VIRAL DEFENSES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 肿瘤坏死因子（TNF）超家族的细胞因子成员在宿主防御病毒病原体中起关键作用。特别是，抗巨细胞病毒（CMV）（一种β疱疹病毒）的有效免疫防御需要光毒素（LT）α-β-LT β受体（LT β R）系统和其他密切相关的细胞因子。人CMV的体外研究和鼠CMV的体内研究均表明，LT β R系统在建立和维持宿主与这种持久性病毒之间的免疫平衡中起关键作用。具体而言，激动剂抗LT β R抗体对LT β R的体内活化可防止淋巴细胞死亡，恢复IFN β水平，重组淋巴组织并延长MCMV感染的L α缺陷型小鼠的存活。这些结果表明，在体内调节LT β R途径可以在这种病毒感染期间恢复免疫平衡。人类CMV感染仍然是一个顽固的临床问题，特别是在免疫受损（化疗或AIDS）患者中，新的证据表明，与持久性病毒（如HCMV）相关的慢性炎症也可能导致心血管疾病。临床上，由于抗病毒药物的功效受到毒性和病毒抗性的限制，因此特别需要有效治疗这种病毒。了解目前可用的抗病毒治疗的局限性提供了强大的动力，以确定新的方法，将提高宿主的免疫反应，同时有效地抑制病毒复制。该提议的目的是检验LT β R是宿主防御人CMV的重要因素的假设。为了实现这3个具体的目标，提出了研究LT细胞因子系统中的恒河猴灵长类动物模型的CMV感染（RhCMV），一个模型，最接近人类CMV感染。在具体目标1中，将使用激动剂和拮抗剂在体外研究LT β R信号传导途径，为具体目标2和3中提出的体内研究提供机制数据。这些体内实验将直接测试LT β R激动剂和拮抗剂作为RhCMV感染调节剂的功效，特别是激动剂抗LT β R抗体改善免疫活性和免疫受损猕猴中感染的能力。这种试剂在猕猴中的成功应该验证这种新的免疫方法作为人类CMV感染的潜在治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cytokine members of the Tumor Necrosis Factor (TNF) Superfamily play key roles in host defense to viral pathogens. In particular, the Lymphotoxin (LT)alpha-beta-LTbeta receptor (LTbetaR) system and other closely related cytokines are required for effective immune defenses against cytomegalovirus (CMV), a beta herpes virus. Both in vitro studies with human CMV and in vivo studies with murine CMV indicate that the LTbetaR system plays a key role in the establishment and maintenance of immunological balance between the host and this persistent virus. Specifically, in vivo activation of the LTbetaR by an agonist anti-LTbetaR antibody can prevent lymphocyte death, restore IFNbeta levels, reorganize lymphoid tissue and extend the survival of MCMV infected, LTalpha-deficient mice. These results indicate that modulating the LTbetaR pathway in vivo can restore immune balance during this viral infection. Human CMV infection remains a stubborn clinical problem especially in immune compromised (chemotherapy or AIDS) patients, and emerging evidence suggests chronic inflammation, associated with persistent viruses like HCMV, may also contribute to cardiovascular disease. Clinically, there exists a particular need for effective treatment of this virus since the efficacy of antiviral drugs has been limited by toxicity and viral resistance. Understanding the limitations of currently available anti-viral treatment provides strong impetus to identify novel approaches that will enhance the host's immune responsiveness while at the same time effectively suppressing virus replication. The goal of this proposal is to test the hypothesis that the LTbetaR is a significant factor in host defense to human CMV. To accomplish this 3 specific aims are proposed to investigate the LT cytokine system in a rhesus macaque primate model of CMV infection (RhCMV), a model which most closely resembles human CMV infection. In specific aim 1, the LTbetaR signaling pathway will be studied in vitro using agonistic and antagonistic reagents to provide mechanistic data for the in vivo studies proposed in specific aims 2 and 3. These in vivo experiments will directly test the efficacy of LT(R agonists and antagonists as modulators of RhCMV infection and in particular the ability of an agonist anti-LTbetaR antibody to ameliorate the infection in both immunocompetent and immunocompromised macaques. The success of this reagent in macaques should validate this novel immunotherapeutic approach as a potential treatment for human CMV infection.