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

摘要 有许多疫苗的例子，导致中和抗体在一个人口，但不是 他人轮状病毒、脊髓灰质炎、霍乱和结核病就是例子。结核病的BCG疫苗接种 越往北接种疫苗，保护率越高。疫苗效力差异的原因是 未知，遗传或环境因素被认为是重要因素。一个有趣的类比 观察到的是，基于人口的CD 4 T细胞测量也因地理位置而异， 北方纬度地区的人比生活在赤道附近的人有更多的CD 4 T细胞。在 我们对HIV感染中CD 4 T细胞丢失机制的研究表明，淋巴细胞中的HIV复制 组织引起胶原形式的成纤维网状细胞网络（FRCn）的炎性损伤 沉积到网络中。FRCn是胸腺外IL-7的主要来源， 网络导致IL-7的产生减少，净结果是T细胞凋亡增加。我们的数据 提示这是HIV感染中CD 4丢失的重要机制。我们推测除了 HIV可能会导致FRCn的炎症损伤，并且可能是CD 4 T细胞耗尽的原因。 生活在热带气候中的人口，特别是发展中经济体。这可能是一个因素， 限制了这些人群的疫苗反应。我们研究了艾滋病毒阴性的人的淋巴结， 我们的初步数据显示，FRCn和CD 4 T细胞群被耗尽， 炎性细胞因子和免疫激活的组织标记物的水平升高。我们给他们打了疫苗 与黄热病疫苗（YFV），并发现中和抗体滴度峰值与我们的定量 FRCn的分析以及炎性细胞因子和免疫活化的测量。这些数据支持我们 淋巴结结构的炎性损伤模型作为疫苗失败的促成因素 在发展中国家的功效。我们现建议在这些初步研究的基础上， 更大的乌干达人队列，但也增加了明尼苏达州的一个队列，我们在那里显示了有限的炎症 对FRCN的损害。我们将进行广泛的免疫学和微生物调查的因素， 持久的免疫反应。我们的假设是，地方性感染以外的艾滋病毒可以导致LN 炎症和胶原蛋白对FRCn的损伤，这将导致CD 4 T细胞耗竭和疫苗受损 应答

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.