MODULATING LYMPHOTOXINS IN PRIMATES FOR VIRAL DEFENSES

调节灵长类动物的淋巴毒素以防御病毒

• 批准号: 8172541
• 负责人: Carl F Ware
• 金额: $ 15.21万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172541
• 关键词: Acquired Immunodeficiency Syndrome; Agonist; Antibodies; Antiviral Agents; Cardiovascular Diseases; Cessation of life; Chronic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Cytomegalovirus; Cytomegalovirus Infections; Data; Equilibrium; Funding; Goals; Grant; Herpesviridae; Host Defense; Immune; Immunocompetent; Immunocompromised Host; Immunotherapeutic agent; In Vitro; Infection; Inflammation; Institution; Lymphocyte; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Modeling; Murid herpesvirus 1; Mus; Pathway interactions; Patients; Play; Primates; Reagent; Research; Research Personnel; Resources; Role; Signal Pathway; Source; System; Testing; Time; Toxic effect; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States National Institutes of Health; Viral; Virus; Virus Diseases; Virus Replication; chemotherapy; cytokine; effective therapy; efficacy testing; in vivo; member; novel; novel strategies; pathogen; prevent; receptor; research study; success; viral resistance

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，淋巴毒素（LT）α-β-LT β受体（LTbetaR）系统和其他密切相关的细胞因子是针对巨细胞病毒（CMV）（一种β疱疹病毒）的有效免疫防御所必需的。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。