MHC class II-restricted immune response in immunosenescence

描述(申请人提供)：初级淋巴器官的免疫衰老的特征是前体细胞的自我更新能力下降，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增加了对感染和癌症的易感性，并降低了对疫苗接种的反应。到目前为止，成功的免疫衰老治疗干预措施仍然难以捉摸，尽管这种疗法具有巨大的潜在好处。为了解决这个问题，我们启动了一项研究，绘制了造血细胞与年龄相关的变化图，以努力确定哪些变化可能适合于治疗干预。我们发现，来自老年人的骨髓细胞前体(CD34+)以及谱系相关的抗原提呈细胞(B细胞和常规树突状细胞(CDC))的一个特征是存在广泛糖化、碳化和脂氧化的蛋白质组。我们假设，修饰后的蛋白质组通过牺牲整体细胞功能和细胞内途径来促进有效的免疫反应，从而有助于免疫衰老。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来定量地确定糖化、脂氧化和碳化蛋白质聚集体的日益碳化的蛋白质组和内体积累如何干扰MHC II类限制性免疫功能。体内和体外实验将在来自三个不同年龄组的小鼠以及年龄从18岁到80岁的人类捐赠者的CDC上进行，以在人类受试者身上验证我们的结果。与其他不能操纵的与年龄相关的修饰(如端粒缩短)不同，我们先前证明了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进行探索，并遵循旨在减少碳化蛋白质组的体外和体内治疗方案。我们预测，由于髓系细胞前体和CDC的半衰期非常短，这使得它们成为减少广泛碳化蛋白质组有害影响的特别合适的靶点。总体的基本目标是改善与年龄相关的细胞蛋白毒性的变化，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.