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HCV感染和相关肝病与对HBV/HAV疫苗的反应受损以及病原体暴露的病态预后更大有关，但是改善这些预防性疫苗反应的策略尚无。尽管HCV疗法的有效性将继续提高，但大多数HCV感染者仍未治疗，并且在未来十年中，改善疫苗反应将仍然是一个重要目标。 HCV对可能导致疫苗反应受损的免疫系统的影响包括幼稚的CD4细胞和树突状细胞（DC）子集数量降低，T-，B-和NK细胞亚群的偏斜以及T细胞耗尽。另外，慢性HCV感染和相关肝病与免疫激活有关（SCD14，LPS，IL-6，HLA-DR+CD38+CD4/8细胞）。新兴证据，包括我们的数据，表明HCV相关的免疫激活（CD16+56-NK子集频率和SCD14）与疾病阶段有关，并且负面预测宿主对IFN治疗的反应。为了鉴定免疫激活的分子驱动因素，我们进行了无偏置的综合血浆蛋白质组分析，以确定免疫激活的相关性。我们的铅分子是等离子体ENPP2（自动昔服）。 HCV感染期间患有晚期肝病的HCV感染升高，并且在HCV感染过程中与CD4激活相关。 ENPP2活性，溶血磷脂酸（LPA）的乘积激活T细胞，提供了一种可以接受治疗性中断的潜在途径。我们提出HCV诱导的免疫激活会损害宿主对新抗原的反应（例如疫苗和新的感染性挑战）。支持这一点，在HIV感染中也存在免疫激活的情况下，我们的初步数据表明，CD4+ HLADR+ CD38+ T细胞频率较高，对宿主对乙型肝炎A疫苗的反应有效预测，而NAIVE CD4+数量较大，积极地预测了反应。最近的证据还表明，免疫激活的标志物对HCV感染期间的HBV疫苗反应有效预测。老年还与感染的易感性和对疫苗的反应受损有关。衰老和慢性HCV感染对免疫系统的综合作用尚未表征，但随着该患者人群持续增长，非常重要。重要的是，我们观察到衰老和慢性HCV感染都会导致更高的ENPP2水平。因此，在我们提出的分析中，ENPP2可能是常见的治疗靶标，也是理想的指标。随着美国和VA HCV感染人群的增长，并且由于发病率（cirhosis，hcc，治疗障碍）在2030年达到高峰，主要是在老年HCV人群中达到峰值，我们建议量化年龄和慢性HCV感染对免疫系统的综合作用，以及对免疫系统对ENPPP2对Neoo Aneoantigiations的影响。在AIM 1中，我们将确定未经处理的HCV，免疫激活，年龄，ENPP2和LPA对新抗原（乙型肝炎A/B疫苗）与召回抗原（TETANUS增强疫苗）反应的独立贡献。在AIM 2中，我们将确定在慢性LCMV感染的情况下，ENPP2抑制对新抗原对新抗原的反应的影响。