The effect of inflammation and damage to lymph node structures on durable protective immunity following vaccination

炎症和淋巴结结构损伤对疫苗接种后持久保护性免疫力的影响

• 批准号: 10335121
• 负责人: Timothy W Schacker
• 金额: $ 65.34万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-25 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335121
• 关键词: Affect; Africa; Antibody Response; Antibody titer measurement; Antigens; Apoptosis; Architecture; BCG Live; Bacille Calmette-Guerin vaccination; Biological Assay; Blood; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Catalogs; Cell Count; Cells; Cholera; Chronic; Collagen; Cytokine Activation; Data; Denmark; Deposition; Developed Countries; Developing Countries; Dose; Environmental Risk Factor; Ethiopia; Europe; European; Exposure to; Fibrosis; Frequencies; Genetic; Geography; Gut associated lymphoid tissue; HIV; HIV Infections; HIV Seronegativity; Helminths; Helper-Inducer T-Lymphocyte; Homeostasis; Human; IL7 gene; Immune response; Immunity; Immunologic Markers; Immunologics; Impairment; Individual; Infection; Inflammation; Inflammatory; Investigation; Laboratories; Lymphoid Tissue; Maintenance; Malaria; Measures; Mediating; Minnesota; Modeling; Mus; Mycobacterium tuberculosis; Peripheral Blood Mononuclear Cell; Persons; Poliomyelitis; Population; Population Study; Process; Production; Reaction; Regulatory T-Lymphocyte; Reticular Cell; Rotavirus; Rotavirus Vaccines; Salmonella; Source; Structure; Switzerland; T cell response; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Thymus Gland; Time; Tissues; Transforming Growth Factor beta; Tropical Climate; Tuberculosis; Uganda; Vaccinated; Vaccination; Vaccines; Virus Replication; Woman; Work; Yellow Fever; Yellow Fever Vaccine; cohort; cytokine; experimental study; geographic difference; immune activation; immune function; lymph nodes; men; microbial; neutralizing antibody; novel; pathogen; population based; response; sample collection; trend; vaccination against tuberculosis; vaccination outcome; vaccine efficacy; vaccine failure; vaccine response; vaccine trial

Abstract There are numerous examples of a vaccine that results in neutralizing antibodies in one population, but not others. Rotavirus, polio, cholera, and tuberculosis (TB) are examples. BCG vaccination for TB has significantly higher rates of protection the further north the vaccine is used. Reasons for differences in vaccine efficacy are unknown with genetic or environmental factors thought to be important factors. An interesting parallel observation is that population based measures of CD4 T cells also vary geographically, with people living in northern latitudes having significantly greater numbers of CD4 T cells than people living close to the equator. In our studies of mechanisms of loss of CD4 T cells in HIV infection, we showed that HIV replication in lymphoid tissues caused inflammatory damage to the Fibroblastic Reticular Cell network (FRCn) in the form of collagen deposition into the network. The FRCn is the primary source of IL-7 outside of the thymus and loss of the network results in decreased production of IL-7 and the net result is increased T cell apoptosis. Our data suggest this is a significant mechanism of CD4 loss in HIV infection. We speculated that infections other than HIV might cause inflammatory damage to the FRCn and might be a reason CD4 T cells are depleted in populations of people living in tropical climates, especially developing economies. This may be a factor in limiting vaccine responses in these populations. We studied lymph nodes in HIV negative people living in Uganda and show in our preliminary data that the FRCn and CD4 T cell populations are depleted and that levels of inflammatory cytokines and tissue markers of immune activation are elevated. We vaccinated them with yellow fever vaccine (YFV) and found the peak neutralizing antibody titer correlated to our quantitative analyses of the FRCn and measures of inflammatory cytokines and immune activation. These data support our model of inflammatory damage to the architecture of lymph nodes as a contributing factor to failure of vaccine efficacy in the developing world. We now propose to build on these preliminary studies by giving YFV to a larger cohort of Ugandans but also to add a cohort in Minnesota where we have shown limited inflammatory damage to the FRCn. We will conduct extensive immunologic and microbial investigations of factors that limit durable immune responses. Our hypothesis is that endemic infections other than HIV can cause LN inflammation and collagen damage to the FRCn which will lead to CD4 T cell depletion and impaired vaccine responses.

抽象的 有很多疫苗可以在一个人群中产生中和抗体的例子，但并非如此 其他的。轮状病毒、脊髓灰质炎、霍乱和结核病 (TB) 就是例子。 BCG 疫苗接种对结核病有显着效果 使用疫苗越北，保护率越高。疫苗功效差异的原因是 未知的遗传或环境因素被认为是重要因素。一个有趣的平行 观察结果是，基于人群的 CD4 T 细胞测量值也因地理位置而异，人们生活在 北纬地区的 CD4 T 细胞数量明显多于赤道附近的地区。在 我们对 HIV 感染中 CD4 T 细胞丢失机制的研究表明，HIV 在淋巴系统中复制 组织以胶原蛋白的形式对成纤维网状细胞网络 (FRCn) 造成炎症损伤 沉积到网络中。 FRCn 是胸腺外 IL-7 的主要来源，并且 网络导致 IL-7 产生减少，最终结果是 T 细胞凋亡增加。我们的数据 表明这是 HIV 感染中 CD4 丢失的一个重要机制。我们推测除了 HIV 可能会对 FRCn 造成炎症损伤，并且可能是 CD4 T 细胞在体内耗尽的原因。 生活在热带气候下的人口，特别是发展中经济体。这可能是一个因素 限制这些人群的疫苗反应。我们研究了生活在艾滋病毒阴性人群的淋巴结 乌干达，我们的初步数据显示 FRCn 和 CD4 T 细胞群已耗尽，并且 炎症细胞因子和免疫激活组织标志物的水平升高。我们给他们接种了疫苗 与黄热病疫苗（YFV），发现峰值中和抗体滴度与我们的定量相关 FRCn 分析以及炎症细胞因子和免疫激活的测量。这些数据支持我们 淋巴结结构炎症损伤模型是疫苗失败的一个促成因素 在发展中国家的功效。我们现在建议在这些初步研究的基础上，将 YFV 提供给 更大的乌干达人队列，还增加了明尼苏达州的队列，我们​​在那里显示出有限的炎症 FRCn 损坏。我们将对限制因素进行广泛的免疫学和微生物研究 持久的免疫反应。我们的假设是，除 HIV 之外的地方性感染也可导致 LN FRCn 的炎症和胶原蛋白损伤将导致 CD4 T 细胞耗竭和疫苗受损 回应。