VACCINE STRATEGIES TO CIRCUMVENT AGE-ASSOCIATED IMMUNE DEFECTS

摘要：应用新的见解开发疫苗策略，以规避 年龄相关性免疫缺陷 随着年龄的增长，幼稚的CD4会出现缺陷，这种缺陷会削弱助手的反应，似乎是主要的限制因素 B细胞反应，包括长寿的免疫球蛋白反应。我们发现，当衰老的小鼠对灭活的 甲型流感疫苗、CD4辅助细胞和B细胞抗体反应通过添加TLR激动剂而大大增强- 激活的树突状细胞(DC)作为抗原提呈细胞(APC)提供最佳的抗原提呈 (Brahmakshtriya et.Al.，2017)。在对小鼠的研究中，我们发现CD4T细胞记忆的程度是 依赖于应答的CD4T细胞在其效应期重新参与与APC的同源相互作用， 5-8天的回复，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)的产生也需要抗原，而TFH是产生长寿B细胞抗体反应的关键 在同一检查站的认可度。因此，记忆的发展依赖于最佳的Ag呈现 无论是最初还是在效应器T细胞达到峰值时。然而，目前使用的许多疫苗，都不能提供后者 AG信号，并且在某些情况下，它们在任一时刻也可能不能提供足够强的信号。我们将测试 这里的前提是，通过用模仿普通疫苗的配方接种疫苗，然后提供 我们已经定义了最佳TFH、B细胞反应和CD4记忆所需的信号。 因此，我们建议，在启动应答时激活APC，然后在随后，在 记忆检查点，将协同增强老化的CD4T细胞的反应，在这样做的过程中 很大程度上绕过了它们与年龄相关的缺陷，这些缺陷阻碍了保护性记忆CD4T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上添加抗原，以提供最佳的抗原 在最初接种疫苗时和在CD4效应器反应的峰值时出现。在目标1中，我们将评估 对a)CD4T细胞效应器和记忆产生的影响，对b)生发中心B细胞产生和 产生抗流感抗体，以及c)产生长寿的浆细胞和B细胞记忆。在《目标2》中，我们 将确定每种治疗方法对抵御致命剂量活流感的长期保护的影响。 我们预测，我们将显示，最初缺乏活性良好的APC和在 效应器阶段检查站限制老年人和年轻人灭活疫苗的效力，并通过 同时提供活化的Ag/APC，疫苗效果会有很大的提高。我们的预测也是一样的 范型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.