MHC class II-restricted immune response in immunosenescence

描述（由申请方提供）：初级淋巴器官的免疫衰老特征为前体细胞自我更新潜力降低以及受年龄相关变化影响的谱系定型细胞的生成。这种免疫力下降的后果是对感染和癌症的易感性增加，以及对疫苗接种的反应减少。到目前为止，成功的免疫衰老治疗干预仍然难以捉摸，尽管这种治疗的巨大潜在利益。为了解决这个问题，我们启动了一项研究，绘制造血细胞中与年龄相关的变化，以确定哪些变化可能适合治疗干预。我们发现，骨髓细胞前体（CD 34+），以及谱系定向抗原呈递细胞（B细胞和传统的树突状细胞（cDC））从老年人群的一个标志，是广泛糖化，羰基化和脂氧化蛋白质组的存在。我们假设，修饰的蛋白质组有助于免疫衰老的整体细胞功能和细胞内的途径，需要安装有效的免疫反应。为了验证这一假设，我们将关注衰老小鼠中的cDC功能。特别是，我们建议使用一系列的生物化学和生物物理学的方法，以定量的方式来确定如何越来越多的羰基化蛋白质组和内体积累的聚集体的糖化，脂氧化和羰基化蛋白质干扰MHC II类限制的免疫功能。将对来自三个不同年龄组的小鼠以及年龄跨度为18至80岁的人类供体的cDC进行体内和体外实验，以验证我们在人类受试者中的结果。与其他年龄相关的变化（例如，端粒缩短），这是不能操纵的，我们以前证明，氧化损伤的蛋白质组是响应于治疗干预，旨在减少其细胞原毒性。因此，MHC II限制性免疫应答将在对照条件下以及在旨在减少羰基化蛋白质组的体外和体内治疗方案后进行探测。我们预测，由于骨髓细胞前体和cDC具有非常短的半衰期，这使得它们成为特别适合用于减少广泛羰基化蛋白质组的有害作用的靶标。总体基本目标是改善细胞蛋白毒性的年龄相关变化，并最终改善cDC介导的适应性免疫应答。

DESCRIPTION (provided by applicant): Immunosenescence of primary lymphatic organs is characterized by a decrease in the self-renewing potential of precursor cells as well as generation of lineage-committed cells affected by age-related changes. The consequences of this immune decline are increased susceptibility to infections and cancer, and reduced responses to vaccinations. Thus far a successful therapeutic intervention for immunosenescence remains elusive, despite the vast potential benefit of such therapy. To address this issue, we initiated a study mapping age-related changes in hematopoietic cells in an effort to determine which changes might be amenable to therapeutic intervention. We found that a hallmark of bone marrow cell precursors (CD34+), as well as lineage committed antigen presenting cells (B cells and conventional dendritic cells (cDC)) from aged populations, is the presence of an extensively glycated, carbonylated and lipoxidated proteome. We hypothesize that the modified proteome contributes to immunosenescence by compromising the overall cellular functionality and intracellular pathways required to mount effective immune responses. To test this hypothesis we will focus on cDC functionality in aging mice. In particular we propose to use a series of biochemical and biophysical approaches to determine in a quantitative manner how the increasingly carbonylated proteome and endosomal accumulation of aggregates of glycated, lipoxidated and carbonylated proteins interfere with MHC class II restricted immune functions. In vivo and in vitro experiments will be performed on cDC from mice of three different age groups as well as human donors with an age spanning from 18 to 80 years old, to validate our results in human subjects. Differently from other age-related modifications (e.g., telomere shortening), which cannot be manipulated, we previously demonstrated that the oxidatively damaged proteome was responsive to therapeutic interventions aimed at decreasing its cellular prototoxicity. Thus, MHC II-restricted immune responses will be probed in control conditions as well as following an in vitro and in vivo therapeutic regimen aimed at decreasing the carbonylated proteome We predict that since myeloid cell precursors and cDC have a very short half-life, this makes them a particularly suitable target for decreasing the harmful effect of an extensively carbonylated proteome. The overall fundamental goal is to improve the age-related changes in cellular proteo- toxicity and ultimately improve cDC-mediated adaptive immune responses.