Alterations in dendritic cell function in aged mice: potential implications for immunotherapy design
Alterations in dendritic cell function in aged mice: potential implications for immunotherapy design
复制标题
DOI：
10.1007/s10522-008-9150-x
复制
发表时间：
2009-02-01
期刊：
影响因子：
4.5
通讯作者：
Bonorino, Cristina
中科院分区：
文献类型：
--
作者：
Paula, Carine;Motta, Adriana;Bonorino, Cristina
已知免疫系统功能随年龄增长而下降，获得性免疫反应，尤其是CD4+T细胞功能似乎是免疫随年龄增长的主要影响点。树突状细胞(DC)是主要的抗原提呈细胞(APC)，在老年人适应性免疫中观察到的缺陷至少部分可能是由于骨髓生成新DC的能力降低或DC功能缺陷所致。在这项研究中，我们研究了老年骨髓(BM)在体外是否有能力产生新的DC，以及老年BM来源的DC对脂多糖(LPS)的反应。由于DC是新开发的抗肿瘤治疗的重要工具，我们还研究了老年DC吞噬和递呈坏死肿瘤细胞抗原的能力。我们发现，与年轻BM相比，老年BM在体外产生的DC更少。老龄小鼠DC经内毒素诱导的DC成熟程度降低，但即使在没有内毒素刺激的情况下，老龄DC仍能产生高水平的肿瘤坏死因子-α。虽然肿瘤细胞的吞噬功能不受年龄的影响，但老年骨髓来源的DC对吞噬功能的反应显示出更高的肿瘤坏死因子-α的产生，而老年DC的肿瘤抗原呈递减少。由于老年DC和年轻DC对吞噬反应的II类上调相似，这可能表明外源性途径中与年龄相关的处理缺陷。这些结果表明，用于产生DC的BM年龄不会损害其吞噬能力或产生TNF-α，但会导致成熟DC产量下降，对内毒素的反应性降低，并降低抗原处理/提呈能力。我们的研究结果对老年人群DC疫苗的优化设计具有一定的指导意义。
It is known that immune system functions decrease with age, and that adaptive immune responses, especially CD4+ T cell function, seem to be the main affected point in immunity with aging. Dendritic cells (DC) are the major antigen presenting cell (APC), and at least part of the defects observed in adaptive immunity of aged individuals could be due to diminished potential of bone marrow to generate new DC, or defects in DC function. In this study, we investigated if the ability of aged bone marrow (BM) to generate new DC in vitro, as well as aged BM-derived DC responses to lypopolysaccharide (LPS). Because DC are important tools in newly developing anti-tumor therapies, we also studied the ability of aged DC to phagocytose and present antigen from necrotic tumor cells. We found that aged BM generated fewer DC in vitro compared to young BM. While LPS-induced DC maturation is reduced in DC of aged mice, a high TNF-alpha production is observed in aged DC even without LPS stimulation. While phagocytosis of tumor cells is not affected by age, and DC derived from aged BM show a higher TNF-alpha production in response to phagocytosis, presentation of tumor antigens was decreased in aged DC. Because class II upregulation in response to phagocytosis was similar between aged and young DC, this could indicate an age associated processing defect in the exogenous pathway. These findings suggest that age of BM used to generate DC does not impair their phagocytic ability or TNF-alpha production, however leads to a decreased yield in mature DC, reduced response to LPS, and diminished antigen processing/presentation potential. Our results are relevant to optimization DC-based vaccine design for aged populations.