VACCINE STRATEGIES TO CIRCUMVENT AGE-ASSOCIATED IMMUNE DEFECTS

摘要：将新的insiderin应用于循环疫苗策略 与年龄相关的免疫缺陷 随着年龄的增长，幼稚CD 4的缺陷会损害辅助反应，似乎是限制免疫应答的主要因素。 B细胞应答，包括长期IgG应答。我们发现，当老年小鼠对失活的 在甲型流感疫苗中，通过加入TLR激动剂， 活化的树突状细胞（DC）作为抗原呈递细胞（APC）提供最佳的抗原呈递 （Brahmakshatriya et.例如，2017年）。在对年轻小鼠的研究中，我们发现CD 4 T细胞记忆的程度是 依赖于应答性CD 4 T细胞在其效应阶段重新参与与APC的同源相互作用， 5-8天的响应，我们称之为“记忆检查点”（Bautista等人，2017年）。最后我们发现， T滤泡辅助细胞（TFH）的产生对于产生长寿命的B细胞Ab应答至关重要，其也需要Ag 在同一个检查站。因此，记忆的发展依赖于最佳的Ag呈递 无论是在最初还是在效应T细胞达到峰值时。然而，目前使用的许多疫苗，未能提供后者， Ag信号，并且在某些情况下，它们也可能在任一时间都不能提供足够强的信号。我们将测试 通过用模拟普通疫苗的制剂接种疫苗，然后提供 我们已经定义了最佳TFH、B细胞应答和CD 4记忆所需的信号。 因此，我们建议，疫苗策略，激活APC在启动反应，然后再次晚些时候， 记忆检查点，将协同作用，以增强老年CD 4 T细胞的反应，并在这样做， 在很大程度上避免了与年龄相关的缺陷，这些缺陷阻碍了保护性记忆性CD 4 T细胞的产生。 和B细胞。我们将使用一种常见的疫苗，灭活流感，并在APC上添加Ag以提供最佳Ag 在初始疫苗接种时和在CD 4效应子应答的峰值时，CD 4抗体可在细胞内呈现。在目标1中，我们将评估 对a）CD 4 T细胞效应子和记忆产生，对B）生殖中心B细胞产生和 产生抗流感的Ab，和c）产生长寿命的浆细胞和B细胞记忆。在目标2中， 将确定每种治疗对长期保护免受致命剂量的活流感的影响。 我们预测，我们将表明，缺乏良好活化的APC最初和持续的Ag呈递在 效应阶段检查点限制了灭活疫苗对老年人和年轻人的效力， 在这两个时间提供活化的Ag/APC，疫苗效力将大大提高。我们预测同样的 范例很可能适用于人类免疫，这些基础研究将证明翻译为 人类

ABSTRACT: APPLYING NEW INSIGHTS TO DEVELOP VACCINE STRATEGIES THAT CIRCUMVENT AGE-ASSOCIATED IMMUNE DEFECTS With age, defects develop in naive CD4 that impair helper responses and seem to be the major factor limiting B cell responses, including long-lived IgG responses. We found that when aged mice respond to inactivated influenza A vaccine, the CD4 helper and B cell Ab responses are much enhanced by adding TLR agonist- activated dendritic cells (DC) as the antigen-presenting cells (APC) to provide optimal Ag presentation (Brahmakshatriya et. al., 2017). In studies in young mice, we found that the extent of CD4 T cell memory is dependent on the responding CD4 T cells re-engaging in a cognate interaction with APC at their effector stage, 5-8 days of their response, which we call the "memory checkpoint" (Bautista et al., 2017). Finally we found that the generation of T follicular helpers (TFH), critical for generating long-lived B cell Ab response also requires Ag recognition at this same checkpoint. Thus development of memory is dependent on optimal Ag presentation both initially and when effector T cells peak. However, many vaccines currently used, fail to provide the later Ag signals and in some cases they also may not provide sufficiently strong signals at either time. We will test this premise here, by vaccinating with formulations mimicking a common vaccine and then providing the signals we have defined that are required for optimal TFH, B cell response and CD4 memory. Thus, we propose that vaccine strategies that activate APC at the initiation of response and then again later, at the memory checkpoint, will synergize to enhance the response of aged CD4 T cells, and in doing so will largely circumvent their age-associated defects that hamper the generation of protective memory CD4 T cells and B cells. We will use a common vaccine, inactivated influenza, and add Ag on APC to provide optimal Ag presentation at initial vaccination and at the peak of CD4 effector response. In Aim 1, we will evaluate the impact on a) CD4 T cells effector and memory generation, on b) germinal center B cells generation and production of Ab to influenza, and on c) generation of long-lived plasma cells and B cell memory. In Aim 2 we will determine the impact of each treatment on long-term protection against lethal doses of live influenza. We predict we will show that the lack of well-activated APC initially and of persistent Ag presentation at the effector stage checkpoint limits the efficacy of inactivated vaccines for the aged and young and that by providing activated Ag/APC at both times, vaccine efficacy will be much improved. We predict the same paradigm is likely to apply to human immunization and that these basic studies will justify translation to humans.