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 有许多疫苗的例子导致一个人群中和抗体，但没有 其他的。轮状病毒，脊髓灰质炎，霍乱和结核病（TB）就是例子。 TB的BCG疫苗接种显着 较高的保护速度较北，使用疫苗。疫苗功效差异的原因是 被认为是重要因素的遗传或环境因素未知。一个有趣的平行 观察结果是，基于人群的CD4 T细胞的测量在地理上也有所不同，人们居住在 北纬度的CD4 T细胞数量明显高于靠近赤道的人。在 我们研究了HIV感染中CD4 T细胞丧失的机制，我们表明淋巴样HIV复制 组织以胶原蛋白形式对成纤维细胞网络网络（FRCN）造成炎症损害 沉积到网络中。 FRCN是胸腺外IL-7的主要来源，损失 网络导致IL-7的产生降低，净结果是T细胞凋亡增加。我们的数据 这表明这是H​​IV感染中CD4丧失的重要机制。我们推测除了感染 HIV可能会对FRCN造成炎症损害，这可能是CD4 T细胞耗尽的原因 居住在热带气候，尤其是发展中经济体中的人群。这可能是一个因素 限制这些人群中的疫苗反应。我们研究了生活在艾滋病毒负面人中的淋巴结 乌干达并在我们的初步数据中显示，FRCN和CD4 T细胞种群耗尽，并且 免疫激活的炎性细胞因子和组织标记水平升高。我们为它们接种了疫苗 使用黄热病疫苗（YFV），发现中和抗体滴度与我们的定量相关 对FRCN的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 淋巴结结构的炎症损害模型，这是导致疫苗失败的因素 发展中国家的功效。现在，我们建议通过将YFV授予这些初步研究 更大的乌干达人队列，但在明尼苏达州增加了一支队列，我们​​显示出有限的炎症性 损坏FRCN。我们将对限制因素进行广泛的免疫学和微生物研究 耐用的免疫反应。我们的假设是，除艾滋病毒以外的其他流行感染可能引起LN FRCN的炎症和胶原蛋白损伤将导致CD4 T细胞耗竭并受损疫苗 回答。