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 HBV/HAV 疫苗反应受损以及病原体暴露后更大的病态结果有关，但尚无改善这些预防性疫苗反应的策略。尽管 HCV 治疗的有效性将继续提高，但绝大多数 HCV 感染者仍未得到治疗，改善疫苗反应仍将是未来十年的重要目标。 HCV 对免疫系统的影响可能导致疫苗反应受损，包括幼稚 CD4 细胞和树突状细胞 (DC) 亚群数量减少、T 细胞、B 细胞和 NK 细胞亚群倾斜以及 T 细胞耗竭。此外，慢性 HCV 感染和相关肝脏疾病与免疫激活（sCD14、LPS、IL-6、HLA-DR+CD38+CD4/8 细胞）相关。包括我们的数据在内的新证据表明，HCV 相关的免疫激活（CD16+56-NK 子集频率和 sCD14）与疾病阶段相关，并负向预测宿主对 IFN 治疗的反应。为了确定免疫激活的分子驱动因素，我们进行了无偏见的综合血浆蛋白质组分析，以确定免疫激活的相关性。我们的先导分子是血浆 ENPP2（自分泌运动因子）。 ENPP2 在患有晚期肝病的 HCV 感染期间升高，并且与 HCV 感染期间的 CD4 激活相关性最好。 ENPP2 活性的产物溶血磷脂酸 (LPA) 可激活 T 细胞，提供一条适合治疗中断的潜在途径。我们认为 HCV 诱导的免疫激活会损害宿主对新抗原（例如疫苗和新的感染性挑战）的反应。支持这一点的是，在 HIV 感染期间也存在免疫激活，我们的初步数据表明较高的 CD4+HLADR+CD38+ T 细胞频率负向预测宿主对甲型肝炎疫苗的反应，而较高的初始 CD4+ 数量正向预测反应。最近的证据还表明，在 HCV 感染期间，免疫激活标记物对 HBV 疫苗反应具有负面预测作用。年龄较大还与感染易感性和疫苗反应受损有关。衰老和慢性丙型肝炎病毒感染对免疫系统的综合影响尚未确定，但随着患者人数的持续增长，其影响非常显着。重要的是，我们观察到衰老和慢性 HCV 感染都会导致较高的 ENPP2 水平。因此，ENPP2 可能是一个常见的治疗靶点，也是我们提出的分析中的理想指标。随着美国和弗吉尼亚州 HCV 感染人群年龄的增长，以及预计到 2030 年，主要在老年 HCV 人群中发病率（肝硬化、HCC、治疗反应受损）达到峰值，我们建议量化年龄和慢性 HCV 感染的综合影响ENPP2 对新抗原反应的影响将指导治疗策略。在目标 1 中，我们将确定未经治疗的 HCV、免疫激活、年龄、ENPP2 和 LPA 对新抗原（甲型/乙型肝炎疫苗）与回忆抗原（破伤风加强疫苗）反应的独立贡献。在目标 2 中，我们将确定慢性 LCMV 感染情况下 ENPP2 抑制对小鼠宿主对新抗原的反应的影响。