Role of ENPP2, immune activation and age on neoantigen response during HCV

ENPP2、免疫激活和年龄对 HCV 期间新抗原反应的作用

• 批准号: 9274915
• 负责人: Donald D Anthony
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274915
• 关键词: Accounting; Address; Age; Aging; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Biological Response Modifiers; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic Hepatitis C; Cirrhosis; Data; Dendritic Cells; Dendritic cell activation; Disease; Effectiveness; Excision; FCGR3B gene; Frequencies; Generations; Goals; HCV Liver Disease; HIV Infections; HLA-DR Antigens; Hepatitis A Vaccines; Hepatitis B; Hepatitis B Vaccines; Hepatitis C; Hepatitis C Prevalence; High Prevalence; Immune; Immune response; Immune system; Immunization; Immunologic Markers; Impairment; Individual; Infection; Interferons; Interleukin-6; Interruption; Kinetics; Lead; Liver diseases; Lymphocytic choriomeningitis virus; Lymphopenia; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Killer Cells; Outcome; Pathway interactions; Patients; Plasma; Population; Predisposition; Preventive vaccine; Process; Proteome; Role; Source; T cell response; T-Lymphocyte; Testing; Tetanus; Therapeutic; Therapeutic Intervention; Vaccines; Veterans; Viral; Virus; Virus Diseases; age effect; aged; base; booster vaccine; exhaustion; hepatitis A-B vaccine; immune activation; improved; in vivo; lysophosphatidic acid; novel therapeutics; pathogen; pathogen exposure; patient population; predicting response; public health relevance; response; therapeutic target; vaccine response

DESCRIPTION (provided by applicant): Chronic HCV infection and associated liver disease are associated with impaired response to HBV/HAV vaccine and greater morbid outcomes upon pathogen exposure, yet strategies to improve these prophylactic vaccine responses are not available. Though effectiveness of HCV therapy will continue to improve, the substantial majority of HCV infected individuals remain untreated, and improving vaccine response will remain an important goal over the coming decade. Effects of HCV on the immune system that may contribute to impaired vaccine response include decreased naive CD4 cell and dendritic cell (DC) subset numbers, skewing of T-, B- and NK-cell subsets, and T cell exhaustion. Additionally, chronic HCV infection and associated liver disease are associated with immune activation (sCD14, LPS, IL-6, HLA-DR+CD38+CD4/8 cells). Emerging evidence, including our data, indicates HCV associated immune activation (CD16+56-NK subset frequency and sCD14) correlates with disease stage and negatively predicts host response to IFN therapy. To identify molecular drivers of immune activation we performed a non-biased comprehensive plasma proteome analysis to determine the correlates of immune activation. Our lead molecule was plasma ENPP2 (autotaxin). ENPP2 was elevated during HCV infection with advanced liver disease, and best correlated with CD4 activation during HCV infection. The product of ENPP2 activity, lysophosphatidic acid (LPA), activates T cells, providing a potential pathway amenable to therapeutic interruption. We propose HCV induced immune activation impairs host response to neoantigen (e.g. vaccine and new infectious challenge). Supporting this, during HIV infection where immune activation also exists, our preliminary data indicate higher CD4+HLADR+CD38+ T cell frequency negatively predicts host response to Hepatitis A vaccine, while greater naive CD4+ numbers positively predict response. Recent evidence also indicates markers of immune activation negatively predict HBV vaccine response during HCV infection. Older age is also associated with susceptibility to infection and impaired response to vaccine. The combined effects of aging and chronic HCV infection on the immune system are not yet characterized, but highly significant as this patient population continues to grow. Importantly, we observed that both aging and chronic HCV infection result in higher ENPP2 levels. Therefore ENPP2 may be a common therapeutic target, and an ideal metric in our proposed analyses. With the growing age of the US and VA HCV infected population, and with morbidity (cirrhosis, HCC, impaired therapy response) projected to peak in 2030 primarily in the aged HCV population, we propose that quantifying the combined effects of age and chronic HCV infection on the immune system, and the impact of ENPP2 on the neoantigen response will guide therapeutic strategies. In Aim 1 we will Determine the independent contributions of untreated HCV, immune activation, age, ENPP2 and LPA to neoantigen (hepatitis A/B vaccine) vs. recall antigen (tetanus booster vaccine) response. In Aim 2 we will Determine the effect of ENPP2 inhibition on murine host response to neoantigen in the setting of chronic LCMV infection.

描述(由申请人提供)： 慢性丙型肝炎病毒感染和相关的肝脏疾病与对乙肝病毒/甲型肝炎疫苗的反应受损和病原体暴露的更大病态结局有关，但目前还没有改善这些预防性疫苗反应的策略。尽管丙型肝炎病毒治疗的有效性将继续提高，但绝大多数丙型肝炎病毒感染者仍未得到治疗，改善疫苗应答仍将是未来十年的重要目标。丙型肝炎病毒对免疫系统的影响可能导致疫苗应答受损，包括初始CD4细胞和树突状细胞(DC)亚群数量减少，T、B和NK细胞亚群倾斜，以及T细胞耗尽。此外，慢性丙型肝炎病毒感染和相关的肝病与免疫激活(sCD14、内毒素、IL-6、人类白细胞抗原DR+CD38+CD4/8细胞)有关。包括我们的数据在内的新证据表明，丙型肝炎病毒相关免疫激活(CD16+56-NK亚群频率和sCD14)与疾病分期相关，并负面预测宿主对干扰素治疗的反应。为了确定免疫激活的分子驱动因素，我们进行了一项无偏见的全面血浆蛋白质组分析，以确定免疫激活的相关因素。我们的先导分子是血浆ENPP2(自体趋化蛋白)。ENPP2在丙型肝炎合并晚期肝病时升高，且在丙型肝炎期间与CD4的激活最相关。ENPP2活性的产物溶血磷脂酸(LPA)激活T细胞，为治疗中断提供了一条潜在的途径。我们认为，丙型肝炎病毒诱导的免疫激活削弱了宿主对新抗原的反应(如疫苗和新的感染挑战)。支持这一点的是，在同时存在免疫激活的艾滋病毒感染期间，我们的初步数据表明，较高的CD4+HLADR+CD38+T细胞频率对宿主对甲型肝炎疫苗的反应具有负面预测作用，而较大的原始CD4+数字则对反应具有积极预测作用。最近的证据也表明，在丙型肝炎病毒感染过程中，免疫激活的标志物可以负向预测乙肝疫苗的免疫应答。年龄较大还与感染易感性和对疫苗的反应受损有关。老龄化和慢性丙型肝炎病毒感染对免疫系统的综合影响尚未得到表征，但随着患者数量的持续增长，这种影响非常显著。重要的是，我们观察到年龄和慢性丙型肝炎病毒感染都会导致ENPP2水平升高。因此，ENPP2可能是一个常见的治疗靶点，也是我们建议的分析中的理想指标。随着美国和VA丙型肝炎病毒感染人群年龄的增长，以及发病率(肝硬变、肝癌、治疗反应受损)预计将在2030年达到峰值，主要发生在老年丙型肝炎病毒人群中，我们建议量化年龄和慢性丙型肝炎病毒感染对免疫系统的综合影响，以及ENPP2对新抗原反应的影响将指导治疗策略。在目标1中，我们将确定未经处理的丙型肝炎病毒、免疫激活、年龄、ENPP2和LPA在新抗原(甲肝/乙肝疫苗)与召回抗原(破伤风加强疫苗)应答中的独立贡献。在目标2中，我们将确定在慢性LCMV感染的背景下，抑制ENPP2对小鼠宿主对新抗原反应的影响。