How IL-10R blockade can resolve persistent viral infections

IL-10R 阻断如何解决持续性病毒感染

• 批准号: 7919813
• 负责人: Matthias G. Von Herrath
• 金额: $ 20.7万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919813
• 关键词: Acute; Address; Adverse effects; Affect; Antibodies; Antigens; Antiviral Agents; Antiviral Response; Autoimmune Process; Autoimmunity; Avidity; B-Lymphocytes; Binding; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Etiology; Cells; Chronic; Clinic; Clinical; Combined Modality Therapy; Communication; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dystroglycan; Ensure; Epitopes; Evaluation; Exposure to; Feedback; Generations; Health; Hepatitis C virus; Hepatitis Viruses; Human; Human Herpesvirus 4; Immune response; Immunity; Immunization; Immunocompromised Host; Immunoglobulin Class Switching; Immunotherapy; In Vitro; Individual; Infection; Interferons; Interleukin-10; Intervention; Investigation; Lead; Liver; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Monitor; Mus; Outcome; Pharmaceutical Preparations; Play; Primates; Principal Investigator; Production; Property; Publishing; Recombinants; Research Personnel; Resolution; Ribavirin; Risk; Role; Signal Transduction; Sorting - Cell Movement; Splenocyte; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Transgenic Organisms; Translating; Translations; Up-Regulation; Upper arm; Ursidae Family; Vaccination; Vaccines; Vaccinia; Variant; Viral; Viral Antigens; Viral Load result; Viral Vaccines; Virus; Virus Diseases; Virus Receptors; Walkers; Weight Gain; Work; anti-viral efficacy; base; cell type; cytokine; immune function; immunopathology; in vivo; innovation; insight; interleukin-10 receptor; killings; macrophage; novel; novel strategies; pre-clinical; preclinical evaluation; receptor; research study; response; working group

DESCRIPTION (provided by applicant): Recently, we made, I believe, a quite remarkable observation that could change how we deal with persistent viral infections. In a murine model of protracted infection that naturally occurs after exposure to the lymphocytic choriomeningitis virus (LCMV) variant Clone 13, we observed that a significant amount of IL-10 is produced, which interestingly coincides with the loss of the systemic cytotoxic T cell response against the virus. In our published studies, systemic administration of an antibody against the IL-10 receptor led to rapid resolution of the persistent infection, as demonstrated by weight gain and reduced viral load in the treated mice, in the absence of systemic side effects or immunopathology. This successful and innovative approach to treating a persistent viral infection constitutes a departure from classical vaccine strategies that have attempted to enhance the anti-viral response by directly inducing or amplifying anti-viral effector T cells. Indeed, such conventional approaches have failed to resolve LCMV Clone 13 infection in previous studies. We therefore suggest that therapeutic agents that block IL-10 receptor may hold great promise for the treatment of persistent viral infections in humans such as HCV and possibly HIV or CMV. In the proposed experiments, we would like to: 1. How chronic infection elicits systemic IL-10 production from DCs, CD4 and CD8 lymphocytes. Based on our findings, our working hypothesis is that CD8a negative DCs are the main drivers of IL-10 production from anti-viral responder cells. This subset is relatively enriched over CD8a positive DCs in chronically infected mice, because CD8 a pos DCs, which drive anti-viral IFN? production, are eliminated. We propose that early viral infection of this subset renders them more susceptible to CTL killing in vivo. 2. Translate the use of IL-10R blockade to the clinic by establishing paradigms for synergy in combination therapies with PD-1/PD-1L blockade, antiviral drugs and anti-viral vaccines A direct comparison of persistent versus acute infection with LCMV will form the basis for this investigation. The results should offer sufficient insight to enable the translation of this novel treatment to human persistent viral infections. In order to assure that our findings reach those groups working on HIV and HCV, cooperations have been established with leading groups in the field.

描述（由申请人提供）：我相信，最近我们进行了一项相当显着的观察，这可能会改变我们处理持续性病毒感染的方式。在暴露于淋巴细胞性脉络丛脑膜炎病毒（LCMV）变体克隆13后自然发生的持久感染的鼠模型中，我们观察到产生了显著量的IL-10，有趣的是，这与针对病毒的全身细胞毒性T细胞应答的丧失相一致。在我们发表的研究中，全身给予抗IL-10受体的抗体导致持续性感染的快速消退，如治疗小鼠的体重增加和病毒载量减少所证明的，而不存在全身副作用或免疫病理学。这种治疗持续性病毒感染的成功和创新的方法构成了对经典疫苗策略的背离，经典疫苗策略试图通过直接诱导或扩增抗病毒效应T细胞来增强抗病毒应答。事实上，在先前的研究中，这种常规方法未能解决LCMV克隆13感染。因此，我们认为阻断IL-10受体的治疗剂可能对治疗人类持续性病毒感染如HCV和可能的HIV或CMV有很大的希望。 在拟议的实验中，我们希望： 1.慢性感染如何刺激DC、CD 4和CD 8淋巴细胞产生系统性IL-10。基于我们的发现，我们的工作假设是CD 8a阴性DC是抗病毒应答细胞产生IL-10的主要驱动因素。在慢性感染的小鼠中，该亚群相对于CD 8a阳性DC富集，因为驱动抗病毒IFN？生产，被淘汰。我们建议，早期病毒感染的这个子集，使他们更容易在体内CTL杀伤。 2.通过建立PD-1/PD-1 L阻断剂、抗病毒药物和抗病毒疫苗联合治疗的协同作用范例，将IL-10 R阻断剂的使用转化为临床 直接比较LCMV的持续与急性感染将构成本研究的基础。这些结果应该提供足够的见解，使这种新的治疗人类持续性病毒感染的翻译。为了确保我们的研究结果能够传达到那些从事艾滋病毒和丙型肝炎病毒工作的团体，我们与该领域的领导团体建立了合作关系。