Pugh Jason L, Foster Sarah A, Sukhina Alona S, Petravic Janka, Uhrlaub Jennifer L, Padilla-Torres Jose, Hayashi Tomonori, Nakachi Kei, Smithey Megan J, Nikolich-Žugich Janko
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ, USA.
Aging Cell. 2016 Aug;15(4):686-93. doi: 10.1111/acel.12478. Epub 2016 Apr 13.
Aging-related decline in immunity is believed to be the main driver behind decreased vaccine efficacy and reduced resistance to infections in older adults. Unrepaired DNA damage is known to precipitate cellular senescence, which was hypothesized to be the underlying cause of certain age-related phenotypes. Consistent with this, some hallmarks of immune aging were more prevalent in individuals exposed to whole-body irradiation (WBI), which leaves no anatomical repository of undamaged hematopoietic cells. To decisively test whether and to what extent WBI in youth will leave a mark on the immune system as it ages, we exposed young male C57BL/6 mice to sublethal WBI (0.5-4 Gy), mimicking human survivor exposure during nuclear catastrophe. We followed lymphocyte homeostasis thorough the lifespan, response to vaccination, and ability to resist lethal viral challenge in the old age. None of the irradiated groups showed significant differences compared with mock-irradiated (0 Gy) animals for the parameters measured. Even the mice that received the highest dose of sublethal WBI in youth (4 Gy) exhibited equilibrated lymphocyte homeostasis, robust T- and B-cell responses to live attenuated West Nile virus (WNV) vaccine and full survival following vaccination upon lethal WNV challenge. Therefore, a single dose of nonlethal WBI in youth, resulting in widespread DNA damage and repopulation stress in hematopoietic cells, leaves no significant trace of increased immune aging in a lethal vaccine challenge model.
免疫功能随年龄增长而下降被认为是老年人疫苗效力降低和抗感染能力减弱的主要驱动因素。已知未修复的DNA损伤会促使细胞衰老，而细胞衰老被认为是某些与年龄相关表型的潜在原因。与此一致的是，免疫衰老的一些特征在接受全身照射（WBI）的个体中更为普遍，全身照射不会留下未受损造血细胞的解剖学储存库。为了明确测试年轻时的WBI是否以及在多大程度上会在免疫系统衰老过程中留下印记，我们将年轻的雄性C57BL/6小鼠暴露于亚致死剂量的WBI（0.5 - 4 Gy）下，模拟核灾难期间人类幸存者的暴露情况。我们在小鼠的整个生命周期中跟踪淋巴细胞稳态、对疫苗接种的反应以及老年时抵抗致命病毒攻击的能力。与假照射（0 Gy）动物相比，各照射组在所测量的参数上均未显示出显著差异。即使是在年轻时接受最高剂量亚致死WBI（4 Gy）的小鼠，也表现出平衡的淋巴细胞稳态、对减毒活西尼罗河病毒（WNV）疫苗的强烈T细胞和B细胞反应，以及在接受致命WNV攻击后接种疫苗后的完全存活。因此，年轻时单次非致死性WBI导致造血细胞广泛的DNA损伤和再增殖应激，在致命疫苗攻击模型中并未留下免疫衰老增加的明显痕迹。
