Metabolic and Immune Responses to Flu Vaccine in Mitochondrial Disease Patients

线粒体疾病患者对流感疫苗的代谢和免疫反应

• 批准号: 8061687
• 负责人: CORNELIA L DEKKER
• 金额: $ 15.36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061687
• 关键词: Address; Adolescent; Adult; Adverse event; Affect; Age; Amino Acids; Antibodies; Antibody Formation; Biochemical Markers; Biological Assay; Biological Markers; Blood; Blood Volume; Blood specimen; CD8B1 gene; Categories; Child; Chronic; Clinical; Clinical Research; Defect; Disease; Encephalopathies; Epitopes; Evaluation; Gene Expression; Glutathione; Glutathione Disulfide; Goals; Hemagglutination; Immune response; Immunity; Immunization; Influenza; Lactic Acidosis; Leukocytes; Licensing; Lymphocyte; Measurement; Measures; Metabolic; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Package Insert; Patients; Pattern; Pilot Projects; Plasma; Play; Property; RNA; Reactive Nitrogen Species; Reactive Oxygen Species; Reduced Glutathione; Risk; Role; Safety; Serum; Signal Transduction; Specificity; Stroke; Sulfhydryl Compounds; Surface; Symptoms; Syndrome; System; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Vaccination; Vaccines; Whole Blood; acylcarnitine; cytokine; immunogenicity; influenza virus vaccine; lymphocyte proliferation; metabolomics; mitochondrial dysfunction; organic acid; public health relevance; response; tandem mass spectrometry; trait; volunteer; young adult

DESCRIPTION (provided by applicant): Each year, 1000 to 4000 children in the U.S. are born with mitochondrial disease. Because symptoms may present at any age, it is not surprising that a temporal association with vaccination may occur. However, little is known about the clinical and immune response to vaccines in patients with mitochondrial disorders. Mitochondria play an important role in T cell activation; we therefore propose a pilot study of the administration of trivalent, inactivated influenza vaccine (TIV) to a group of 15 adolescent and adult patients with MELAS syndrome, a specific mitochondrial disorder, to describe solicited adverse events, detailed metabolic responses and an in-depth evaluation of immune responses to TIV. These responses will be compared with those of healthy control volunteers 18-30 yrs of age. Blood samples on all subjects will be taken prior to immunization, at 6h, 5-7 days and 25-28 days following immunization. In Aim 1, biomarkers of mitochondrial function in blood will be described to determine if TIV causes oxidative stress. This will include GC and tandem mass spectrometric assays for metabolomic profiling in plasma with measurement of reduced (GSH) and oxidized (GSSG) glutathione, organic acids, amino acids, acylcarnitines and other metabolites; FACS assays for intracellular GSH, intracellular reactive oxygen species, intracellular reactive nitrogen species and surface thiols. In Aim 2, immune response will be examined to assess if traits change with mitochondrial dysfunction and age, which traits correlate with a robust or poor antibody immune response and whether antibody and T cell responses are affected by mitochondrial dysfunction. This will be accomplished by analysis of 42 cytokines in serum using the Luminex system, white blood cell subsetting into 15 separate categories, gene expression studies performed on RNA using the Agilent 44K microarray, lymphocyte proliferation studies in the different T cell subsets with cytokine analysis of supernatants, influenza-specific T cell responses with measurement of cytokines, and multiplex cell signaling using phosphoflow assays. This proposal is unique in that it examines for the first time the effects of immunization on the metabolic status of patients who are at risk for metabolic decompensation following oxidative stress, and whether MELAS syndrome affects the T cell and antibody response to TIV. Analysis of these results will allow for selection of certain assays that can be tested in subsequent studies of younger patients where smaller blood volumes limit the number of assays that can be done. PUBLIC HEALTH RELEVANCE: This proposed pilot study will provide important new information about how patients with MELAS syndrome, a form of mitochondrial disease, tolerate immunization with flu vaccine in comparison with healthy young adult controls. Special studies of biomarkers in the blood will tell us if immunization causes oxidative stress in these groups and if so, whether this might be related to adverse events. Lastly, intense evaluation of immune responses in these groups will look for biomarkers that predict protective responses to influenza vaccine and that might be affected by this mitochondrial disorder.

描述（由申请人提供）：美国每年有1000至4000名儿童出生时患有线粒体疾病。由于任何年龄都可能出现症状，因此可能与疫苗接种存在时间关联并不奇怪。然而，对线粒体疾病患者对疫苗的临床和免疫反应知之甚少。线粒体在T细胞活化中起着重要作用;因此，我们提出了一项对15名患有MELAS综合征（一种特定的线粒体疾病）的青少年和成人患者进行三价灭活流感疫苗（TIV）给药的初步研究，以描述征集性不良事件，详细的代谢反应和对TIV免疫反应的深入评价。将这些反应与18-30岁的健康对照志愿者的反应进行比较。所有受试者的血样将在免疫前、免疫后6小时、5-7天和25-28天采集。在目标1中，将描述血液中线粒体功能的生物标志物以确定TIV是否引起氧化应激。这将包括用于血浆代谢组学分析的GC和串联质谱分析，测量还原型（GSH）和氧化型（GSSG）谷胱甘肽、有机酸、氨基酸、酰基肉毒碱和其他代谢物;用于细胞内GSH、细胞内活性氧、细胞内活性氮和表面硫醇的FACS分析。在目的2中，将检查免疫应答以评估性状是否随线粒体功能障碍和年龄而变化，这些性状与强或弱的抗体免疫应答相关，以及抗体和T细胞应答是否受线粒体功能障碍的影响。这将通过使用Luminex系统分析血清中的42种细胞因子、将白色血细胞分成15个单独的类别、使用Agilent 44 K微阵列对RNA进行基因表达研究、在不同T细胞亚群中进行淋巴细胞增殖研究并对上清液进行细胞因子分析、通过测量细胞因子进行流感特异性T细胞应答以及使用磷酸流测定进行多重细胞信号传导来实现。该提案的独特之处在于，它首次研究了免疫接种对氧化应激后代谢失代偿风险患者代谢状态的影响，以及MELAS综合征是否影响T细胞和TIV抗体反应。对这些结果的分析将允许选择可以在年轻患者的后续研究中进行测试的某些测定，其中较小的血液体积限制了可以进行的测定的数量。 公共卫生相关性：这项拟议的试点研究将提供重要的新信息，说明MELAS综合征（一种线粒体疾病）患者与健康年轻人对照组相比如何耐受流感疫苗免疫。对血液中生物标志物的特殊研究将告诉我们，免疫是否会导致这些群体的氧化应激，如果是，这是否可能与不良事件有关。最后，对这些人群免疫反应的深入评估将寻找预测流感疫苗保护性反应的生物标志物，这些生物标志物可能受到这种线粒体疾病的影响。