MODULATING LYMPHOTOXINS IN PRIMATES FOR VIRAL DEFENSES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肿瘤坏死因子超家族的细胞因子在宿主对病毒病原体的防御中起着关键作用。特别是，淋巴毒素(LT)α-β-LTbetaR(LTbetaR)系统和其他密切相关的细胞因子是有效免疫防御巨细胞病毒(CMV)所必需的。对人CMV的体外研究和对小鼠CMV的体内研究都表明，LTbetaR系统在建立和维持宿主和这种持久病毒之间的免疫平衡方面发挥着关键作用。具体地说，在体内，由激动剂抗LTbetaR抗体激活LTbetaR可以防止淋巴细胞死亡，恢复IFNβ水平，重组淋巴组织，并延长MCMV感染的LTalpha缺陷小鼠的生存时间。这些结果表明，在体内调节LTbetaR途径可以在病毒感染期间恢复免疫平衡。人类巨细胞病毒感染仍然是一个顽固的临床问题，特别是在免疫功能低下的(化疗或艾滋病)患者中，新出现的证据表明，与HCMV等持续病毒相关的慢性炎症也可能导致心血管疾病。在临床上，由于抗病毒药物的疗效受到毒性和病毒耐药性的限制，因此特别需要有效地治疗这种病毒。了解目前可用的抗病毒治疗的局限性，为寻找新的方法提供强大的动力，这些方法将增强宿主的免疫反应性，同时有效地抑制病毒复制。这一建议的目的是验证LTbetaR是宿主防御人类CMV的重要因素这一假设。为了实现这三个特定目标，我们提出了在巨细胞病毒感染猕猴灵长类动物模型(RhCMV)中研究LT细胞因子系统的建议，该模型最接近于人类CMV感染。在特定目标1中，将使用激动剂和拮抗剂在体外研究LTbetaR信号通路，为特定目标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(R激动剂和拮抗剂)作为RhCMV感染调节剂的有效性，特别是激动剂抗LTbetaR抗体改善免疫活性和免疫受损猕猴感染的能力。这种试剂在猕猴身上的成功应该验证这种新的免疫治疗方法作为一种潜在的人类巨细胞病毒感染的治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.