MHC class II-restricted immune response in immunosenescence

描述（由申请人提供）：原发性淋巴器官的免疫衰老的特征是前体细胞自我更新潜力的减少，以及受年龄相关变化影响的谱系承诺细胞的产生。这种免疫力下降的后果是对感染和癌症的易感性增加，对疫苗接种的反应减少。迄今为止，尽管这种疗法有巨大的潜在益处，但成功的免疫衰老治疗干预仍然难以捉摸。为了解决这个问题，我们启动了一项研究，绘制了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，来自老年人群的骨髓细胞前体（CD34+）以及谱系承诺的抗原呈递细胞（B细胞和常规树突状细胞（cDC））的一个标志是广泛糖基化、羰基化和脂氧化的蛋白质组的存在。我们假设，修饰的蛋白质组通过损害整体细胞功能和建立有效免疫应答所需的细胞内通路来促进免疫衰老。为了验证这一假设，我们将重点研究衰老小鼠的cDC功能。特别是，我们建议使用一系列生化和生物物理方法，以定量的方式确定越来越多的羰基化蛋白质组和糖基化、脂氧化和羰基化蛋白质聚集的内体积累如何干扰MHC II类限制性免疫功能。体内和体外实验将在三个不同年龄组的小鼠以及年龄从18岁到80岁的人类捐赠者身上进行，以验证我们在人类受试者身上的结果。与其他无法控制的年龄相关修饰（如端粒缩短）不同，我们之前证明氧化损伤的蛋白质组对旨在降低其细胞原毒性的治疗干预有反应。因此，MHC ii限制性免疫反应将在对照条件下以及体外和体内治疗方案中进行探索，旨在降低羰基化蛋白质组。我们预测，由于骨髓细胞前体和cDC具有非常短的半衰期，这使它们成为降低广泛羰基化蛋白质组有害影响的特别合适的靶标。总体的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介导的适应性免疫反应。

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.