Dendritic cell mediated modulation of tolerance by apoptotic cells in aging

树突状细胞介导衰老过程中凋亡细胞对耐受性的调节

基本信息

批准号：
7268013
负责人：
Anshu Agrawal
金额：
$ 15.18万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268013
关键词：
5-(6)-carboxyfluorescein diacetate succinimidyl ester Age Aging Antigen Presentation Antigen-Presenting Cells Antigens Apoptosis Apoptotic Applications Grants Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity Biological Assay CD36 gene CD80 gene Cell Aging Cell membrane Cells Coculture Techniques Complement Receptor Condition Cytolysis Data Dendritic Cells Dendritic cell activation Down-Regulation Dyes Enzyme-Linked Immunosorbent Assay Flow Cytometry Human Human Activities Immune system Immunity Impairment Individual Infection Inflammatory Ingestion Interleukin-12 Lead Ligation Lupus Maintenance Major Histocompatibility Complex Malignant Neoplasms Measures Mediating Mediator of activation protein Nuclear Antigens Pathology Peripheral Phenotype Play Production Quantitative Evaluations Research Personnel Rheumatoid Arthritis Role Sampling Self Tolerance Signal Pathway Signal Transduction Signaling Molecule Staining method Stains T-Lymphocyte T-Lymphocyte Subsets TNFRSF5 gene Up-Regulation Western Blotting aged autoreactivity base cell age cytokine extracellular immune function immunosenescence lymph nodes microbial monocyte programs receptor expression uptake

项目摘要

DESCRIPTION (provided by applicant: Aged humans are more susceptible to infections and cancer as a consequence of progressive decline in immune functions with aging. Paradoxically, this decline in immune function is associated with increased reactivity towards self or endogenous antigens. There is increased autoantibody production and propensity towards developing autoimmune diseases with age. This suggests a loss of self tolerance associated with immunosenescence. Amongst the cells of the immune system, dendritic cells are the most potent of antigen presenting cells that are critical mediators of both tolerance and immunity. Immature dendritic cells constantly sample antigens from dying cells in the periphery and present them to T cells in the absence of costimulation, leading to T cell tolerance. Uptake and ingestion of apoptotic cells by dendritic cells is thus considered to be one of the major mechanisms responsible for peripheral self tolerance. Apoptosis is increased in aged humans and during apoptosis, nuclear antigens are expressed on cell membranes and may serve to induce autoreactivity if apoptotic cells are not swiftly and efficiently cleared. Our preliminary data suggest that dendritic cells in aging display a more mature phenotype and reduced uptake of apoptotic cells compared to their young counterparts. Therefore our hypothesis is that the peripheral tolerance inducing capacity of dendritic cells is altered with age and plays a major role in increased autoimmunity associated with aging. The following are the specific aims of the project- 1) to determine the mechanisms for impaired uptake of apoptotic cells in human monocyte- derived dendritic cells with age. 2) to analyze a role of dendritic cells in age-associated alterations in the induction and maintenance of peripheral tolerance.

描述（由申请人提供：由于随着年龄的增长，免疫功能逐渐下降，老年人更容易受到感染和癌症。矛盾的是，这种免疫功能的下降与对自身或内源性抗原的反应性增加有关。自身抗体的产生增加以及随着年龄的增长而发生自身免疫性疾病的倾向，这表明与免疫衰老相关的自我耐受性的丧失，在免疫系统的细胞中，树突状细胞是最有效的关键抗原呈递细胞。未成熟的树突状细胞不断从周围死亡的细胞中取样抗原，并在没有共刺激的情况下将其呈递给 T 细胞，从而导致树突状细胞对凋亡细胞的吸收和摄取。是导致外周自身耐受的主要机制之一。在老年人中，细胞凋亡增加，并且在细胞凋亡过程中，核抗原在细胞膜上表达，如果凋亡细胞不表达，则可能会诱导自身反应。迅速有效地清除。我们的初步数据表明，与年轻的树突状细胞相比，衰老时的树突状细胞表现出更成熟的表型，并且对凋亡细胞的摄取减少。因此，我们的假设是，树突状细胞的外周耐受诱导能力随着年龄的增长而改变，并且在与衰老相关的自身免疫增强中发挥着重要作用。该项目的具体目标如下： 1) 确定人单核细胞来源的树突状细胞随年龄增长而摄取凋亡细胞受损的机制。 2）分析树突状细胞在诱导和维持外周耐受性的年龄相关变化中的作用。