Ananya Ananya, Holden Kaitlyn G, Gu Zhiling, Nettleton Dan, Mallapragada Surya K, Wannemuehler Michael J, Kohut Marian L, Narasimhan Balaji
Nanovaccine Institute, Iowa State University, Ames, IA, 50011, USA.
Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, 50011, USA.
Immun Ageing. 2023 Mar 9;20(1):10. doi: 10.1186/s12979-023-00332-0.
The loss in age-related immunological markers, known as immunosenescence, is caused by a combination of factors, one of which is inflammaging. Inflammaging is associated with the continuous basal generation of proinflammatory cytokines. Studies have demonstrated that inflammaging reduces the effectiveness of vaccines. Strategies aimed at modifying baseline inflammation are being developed to improve vaccination responses in older adults. Dendritic cells have attracted attention as an age-specific target because of their significance in immunization as antigen presenting cells that stimulate T lymphocytes.
In this study, bone marrow derived dendritic cells (BMDCs) were generated from aged mice and used to investigate the effects of combinations of adjuvants, including Toll-like receptor, NOD2, and STING agonists with polyanhydride nanoparticles and pentablock copolymer micelles under in vitro conditions. Cellular stimulation was characterized via expression of costimulatory molecules, T cell-activating cytokines, proinflammatory cytokines, and chemokines. Our results indicate that multiple TLR agonists substantially increase costimulatory molecule expression and cytokines associated with T cell activation and inflammation in culture. In contrast, NOD2 and STING agonists had only a moderate effect on BMDC activation, while nanoparticles and micelles had no effect by themselves. However, when nanoparticles and micelles were combined with a TLR9 agonist, a reduction in the production of proinflammatory cytokines was observed while maintaining increased production of T cell activating cytokines and enhancing cell surface marker expression. Additionally, combining nanoparticles and micelles with a STING agonist resulted in a synergistic impact on the upregulation of costimulatory molecules and an increase in cytokine secretion from BMDCs linked with T cell activation without excessive secretion of proinflammatory cytokines.
These studies provide new insights into rational adjuvant selection for vaccines for older adults. Combining appropriate adjuvants with nanoparticles and micelles may lead to balanced immune activation characterized by low inflammation, setting the stage for designing next generation vaccines that can induce mucosal immunity in older adults.
与年龄相关的免疫标志物的丧失，即免疫衰老，是由多种因素共同作用引起的，其中之一是炎症衰老。炎症衰老与促炎细胞因子的持续基础生成有关。研究表明，炎症衰老会降低疫苗的效力。旨在改变基线炎症的策略正在被开发，以改善老年人的疫苗接种反应。树突状细胞作为一种年龄特异性靶点受到关注，因为它们作为刺激T淋巴细胞的抗原呈递细胞在免疫中具有重要意义。
在本研究中，从老年小鼠中生成骨髓来源的树突状细胞（BMDC），并用于研究佐剂组合的效果，包括Toll样受体、NOD2和STING激动剂与聚酸酐纳米颗粒和五嵌段共聚物胶束在体外条件下的作用。通过共刺激分子、T细胞激活细胞因子、促炎细胞因子和趋化因子的表达来表征细胞刺激。我们的结果表明，多种TLR激动剂显著增加了培养物中与T细胞激活和炎症相关的共刺激分子表达和细胞因子。相比之下，NOD2和STING激动剂对BMDC激活只有中等程度的影响，而纳米颗粒和胶束本身没有影响。然而，当纳米颗粒和胶束与TLR9激动剂联合使用时，观察到促炎细胞因子的产生减少，同时保持T细胞激活细胞因子的产生增加并增强细胞表面标志物表达。此外，将纳米颗粒和胶束与STING激动剂联合使用对共刺激分子的上调产生协同作用，并增加与T细胞激活相关的BMDC的细胞因子分泌，而不会过度分泌促炎细胞因子。
这些研究为老年人疫苗合理佐剂选择提供了新的见解。将合适的佐剂与纳米颗粒和胶束结合可能导致以低炎症为特征的平衡免疫激活，为设计能够在老年人中诱导黏膜免疫的下一代疫苗奠定基础。
