Impact of Senolytics on Aged Vaccine Responses

项目摘要 尽管广泛接种疫苗，流感（流感）仍然是老年人死亡的主要原因。 接种疫苗是预防传染病最有效的方法。然而，老年人的调节失调， 降低疫苗效力并使他们处于严重感染和死亡风险的免疫反应。老年 成年人患流感后，T细胞增殖减少，B细胞反应受损，抗体滴度降低 预防针目前提高老年人疫苗效力的方法针对免疫缺陷的单一缺陷。 反应，并未能完全拯救反应。接种疫苗需要多种复杂的协调 细胞类型和组织;因此，一种针对衰老的整体生物学的方法，符合老年科学 假设，可能更适合于改善老年人的疫苗保护和免疫反应。 衰老细胞积累是衰老的标志，并且随着年龄的增长在各种组织中明显。虽然这些 细胞的特征在于细胞周期停滞的大部分不可逆状态，它们保持代谢活性， 重要是，它分泌一种炎症细胞因子和趋化因子的异质混合物， 组织功能障碍和损伤，被称为衰老相关分泌表型（SASP）。 衰老细胞和SASP的积累创造了促炎环境，并在炎症反应中起因果作用。 许多与年龄有关的疾病。CD 4 T细胞和B细胞，负责稳健疫苗接种的主要细胞 反应，对它们的微环境非常敏感。因此，我们建议， 衰老细胞和它们的SASP驱动疫苗接种应答随衰老而减弱。 重要的是，已经开发出特异性杀死衰老细胞的药物，称为senolytics， 仅间歇给药以消除衰老细胞并减轻SASP。的安全性和疗效 在小鼠研究中已经显示出抗衰老药物的作用，并且可以减轻一系列与年龄有关的疾病。人类 初步研究支持了它们在某些病理学中的安全性和临床效用。然而， 目前尚未研究senolytics对老年人群接种疫苗应答的影响。总体假设 在这个提议中，衰老细胞和SASP在受损流感疫苗接种中起着因果作用 衰老的反应，衰老细胞的药理学清除将改善疫苗接种 应答我们将测试这一假设，通过治疗年轻和老年小鼠与衰老药物之前， 预防针我们将利用两种不同的疫苗接种方法，重组流感核蛋白， 保护性免疫和佐剂灭活流感病毒诱导中和免疫，然后感染小鼠 询问细胞介导的和体液的疫苗接种反应。此外，我们将测试我们的假设 通过测定衰老细胞条件培养基如何影响人T和B细胞应答， 文化这些方法将使我们能够检查细胞衰老在受损疫苗接种中的作用 反应与老化，并调查翻译效用的senolytic药物作为疫苗接种前的佐剂。

PROJECT SUMMARY Despite widespread vaccination, influenza (flu) remains a leading cause of death among older adults. Vaccination is the most effective way to prevent infectious disease. However, older adults have dysregulated immune responses that reduce vaccine efficacy and leave them at risk for severe infection and death. Older adults have reduced T cell proliferation, impaired B cell responses, and decreased antibody titers following flu vaccination. Current methods to improve vaccine efficacy in older adults target singular deficits in immune responses and fail to completely rescue responses. Vaccination requires a complex coordination of multiple cell types and tissues; thus an approach that targets the overall biology of aging, in line with the geroscience hypothesis, may be more appropriate for improving vaccine protection and immune responses in older adults. Senescent cell accumulation is a hallmark of aging and evident in various tissues with age. Although these cells are characterized by a mostly irreversible state of cell cycle arrest, they remain metabolically active and importantly, secrete a heterogeneous cocktail of inflammatory cytokines and chemokines that contribute to tissue dysfunction and damage that is coined senescence associate secretory phenotype (SASP). Accumulation of senescent cells and SASP create pro-inflammatory environments and have a causal role in many age-related disorders. CD4 T cells and B cells, the main cells responsible for robust vaccination responses, are extremely sensitive to their microenvironments. Thus, we propose that accumulation of senescent cells and their SASP drive diminished vaccination responses with aging. Importantly, drugs that specifically kill senescent cells, termed senolytics, have been developed and require only intermittent administration to eliminate senescence cells and mitigate the SASP. The safety and efficacy of senolytics have been shown in mouse studies and can alleviate a range of age-related diseases. Human pilot studies have supported their safety and clinical utility in certain pathologies. However, the impact of senolytics on vaccination responses in aged populations has not yet been examined. The overall hypothesis in this proposal is that senescent cells and the SASP play a causal role in impaired flu vaccination responses with aging and that pharmacological clearance of senescent cells will improve vaccination responses. We will test this hypothesis by treating young and aged mice with senolytic drugs prior to vaccination. We will utilize two different vaccination methods, recombinant flu nucleoprotein to induce protective immunity and adjuvanted inactivated flu to induce neutralizing immunity, and then infect mice with flu to interrogate both cell-mediated and humoral vaccination responses. Additionally, we will test our hypothesis in human cells by determining how senescent cell conditioned media impact human T and B cells responses in culture. These approaches will allow us to examine the role of cellular senescence in impaired vaccination responses with aging and investigate the translational utility of senolytic drugs as a pre-vaccination adjuvant.