MHC class II-restricted immune response in immunosenescence

免疫衰老中 MHC II 类限制性免疫反应

基本信息

批准号：
9269951
负责人：
LAURA SANTAMBROGIO
金额：
$ 34.24万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269951
关键词：
Address Affect Age Aging Antigen-Presenting Cells Antigens B-Lymphocytes Biochemical Biological Biological Assay Blood Body Weight Bone Marrow Cells CD34 gene Cathepsins Cell physiology Cells Complex Dendritic Cells Elderly FDA approved Generations Goals Half-Life Heat shock proteins Hematopoietic Histocompatibility Antigens Class II Human I-antigen Immune Immune response Immune system In Vitro Individual Infection Invaded Laboratories Length Link Lymphatic MHC Class II Genes Malignant Neoplasms Mediating Mind Modeling Modification Mus Myelogenous Myeloid Cells Nodal Organ Organelles Oxidative Stress Paraquat Pathway interactions Peptides Phagocytosis Predisposition Production Proteins Proteome Regimen Reporting Series Surface System Telomerase Telomere Shortening Testing Therapeutic Therapeutic Intervention Time Treatment Efficacy Vaccination Vaccines adaptive immune response age group age related aging population antigen processing biophysical techniques comparative dosage experimental study functional decline glycation human subject human very old age (85+)immune function immunosenescence improved in vivo oxidation oxidative damage pathogen precursor cell proteotoxicity public health relevance regenerative response self-renewal subcutaneous trafficking treatment effect vaccine response

项目摘要

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.

描述（由申请人提供）：原代淋巴器官的免疫衰老的特征是前体细胞的自我更新潜力的降低以及受年龄相关变化影响的谱系谱系细胞的产生。这种免疫下降的后果是增加对感染和癌症的敏感性，以及对疫苗接种的反应减少。迄今为止，尽管这种治疗具有巨大的潜在益处，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映射造血细胞与年龄相关的变化，以确定哪些变化可能适合治疗干预。我们发现，来自老年群体的骨髓细胞前体（CD34+）的标志以及谱系所承诺的抗原呈递细胞（B细胞和常规的树突状细胞（CDC））是广泛糖化，羰基化，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通过损害了安装有效免疫反应所需的总体细胞功能和细胞内途径，从而有助于免疫衰老。为了检验这一假设，我们将重点介绍老化小鼠的CDC功能。特别是我们建议使用一系列的生化和生物物理方法以定量的方式确定越来越多的羰基蛋白质组和内体积累的聚集体如何与MHC II限制性免疫功能相互作用。体内和体外实验将对来自三个不同年龄段的小鼠以及年龄从18岁到80岁的人类捐助者的CDC进行，以验证我们在人类受试者中的结果。与其他与年龄相关的修饰（例如，端粒缩短）不同，无法操纵，我们先前证明，氧化受损的蛋白质组对旨在降低其细胞原始毒性的治疗干预措施有反应。因此，MHC II限制的免疫反应将在对照条件下进行探测，并遵循体外和体内治疗方案，旨在降低碳纤维化的蛋白质组，我们预测，由于髓样细胞前体和CDC具有很短的半寿命，因此这使它们成为降低较大效果的较短效应的靶标，这使得它们成为了扩展型的效应。总体基本目标是改善与年龄相关的细胞蛋白毒性变化，并最终改善CDC介导的适应性免疫反应。