Clinical Studies Of Abnormal Host Defense

宿主防御异常的临床研究

基本信息

项目摘要

1) Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the multicomponent NADPH oxidase (phagocyte oxidase, NOX2) complex. During the past FY, through collaboration with the Neutrophil Monitoring Laboratory (NML) managed by Douglas Kuhns, PhD ( Leidos, Inc.), we provided molecular diagnoses using immunodetection of components of the NADPH oxidase for 4 p47phox-deficient- and 12 gp91phox-deficient subjects. Nucleic acid sequencing determined the mutations in 33 patients and family members including the rarest form, p40phox deficiency. The NML has also provided molecular diagnosis of other patients with immunodeficiencies due to mutations in CXCR4, ITGB2, WDR1, and PADI4. Dr. Kuhns has developed a novel approach to determining p47 mutations relying on digital droplet PCR (manuscript in prep). During this FY, we collaborated with the Genetic Immunotherapy Section of the LHD to demonstrate novel gene therapy approaches to correct induced pluripotent stem cells from CGD patients (Merling et al., Molecular Therapy 2015). We are currently collaborating with the Human Immunological Disease Unit of the LHD to evaluate innate immune function in phagocytes from several patients. 2) Our group continues its clinical and laboratory studies of the emerging Gram-negative CGD pathogen, Granulibacter bethesdensis. During FY15, we screened 11 CGD samples and 15 normal samples for seropositivity toward G. bethesdensis methanol dehydrogenase, an immunodominant antigen. We continue to monitor seropositivity in culture-confirmed patients to evaluate our hypothesis that this organism can establish persistent, clinically unapparent infections. 3) During FY15, we published a paper describing data from NIH Protocol #10-I-0029 Non-invasive Assessment of Atherosclerosis in Patients with CGD and other Disorders of the Immune System (current total = 85 subjects). Atherosclerosis is caused, in part, by inflammation in the vasculature and over production of reactive oxygen species (ROS) has been implicated in pathogenesis of this disease. We hypothesized that CGD patients, who have deficient production of reactive oxygen species by their phagocytes and other cells, may be protected from developing atherosclerosis. The primary endpoint of this study was the assessment of atherosclerotic plaque formation/calcium deposition in the carotid and coronary arteries by CT, MRI and other imaging methodologies, in these and other patients with in-born disorders of immune function. We found significantly smaller carotid vessel wall volumes, a pre-clinical measure of atherosclerosis, in CGD patients compared to age- and sex-matched control subjects. This finding was published in Circulation (Sibley et al.). We continue to study patients on this protocol and have focused on carriers of X-linked CGD reasoning that these otherwise healthy individuals should have subnormal amounts of ROS and that this may be protective in this somewhat older cohort of subjects. This current effort will prove the hypothesis that lower levels of ROS production are protective although the situation in the X-linked CGD carriers differs from the CGD patients in that some cells are normal and some are abnormal. Simultaneously, we are collaborating with the National Center for Advancing Translational Sciences (NCATS), involving the development of high throughput assays for NADPH oxidase activity to permit large-scale screening of chemical inhibitors of NOX2. (4) In normal PMN, activation of NOX2 results in a rapid (within seconds to minutes) depletion of NADPH and hypoxia. Given the central roles of oxygen and NAPDH in metabolism, we compared the metabolomes of PMN before and after activation of NOX2 in a pilot study and found unexpected alterations in PMN metabolism. We are repeating these studies in PMN from patients with CGD to determine the exact role of ROS in these processes.
1)慢性肉芽肿病(CGD)是由多组分NADPH氧化酶(吞噬细胞氧化酶,NOX 2)复合物突变引起的原发性免疫缺陷。在过去的财政年度,通过与道格拉斯库恩斯博士(Leidos,Inc.)管理的中子监测实验室(NML)合作,我们对4例p47 phox缺陷型和12例gp 91 phox缺陷型患者的NADPH氧化酶组分进行了免疫检测,从而提供了分子诊断。 核酸测序确定了33名患者和家庭成员的突变,包括最罕见的p40 phox缺陷。 NML还为其他因CXCR 4、ITGB 2、WDR 1和PADI 4突变而导致免疫缺陷的患者提供了分子诊断。 Kuhns博士开发了一种依靠数字液滴PCR确定p47突变的新方法(手稿在准备中)。在本财政年度,我们与LHD的遗传免疫治疗部门合作,展示了新的基因治疗方法,以纠正来自CGD患者的诱导多能干细胞(Merling et al.,Molecular Therapy 2015)。 我们目前正在与LHD的人类免疫疾病单位合作,以评估几个患者吞噬细胞的先天免疫功能。 2)我们的小组继续其临床和实验室研究的新兴革兰氏阴性CGD病原体,贝氏颗粒杆菌。在2015财年,我们筛选了11份CGD样本和15份正常样本,以检测G. Bethesdensis甲醇脱氢酶,免疫显性抗原。 我们继续监测培养证实的患者的血清阳性,以评估我们的假设,即这种微生物可以建立持续的,临床上不明显的感染。 3)在2015财年,我们发表了一篇论文,描述了NIH方案#10-I-0029 CGD和其他免疫系统疾病患者动脉粥样硬化的无创评估(当前总计= 85例受试者)的数据。 动脉粥样硬化部分是由脉管系统中的炎症引起的,并且活性氧(ROS)的过度产生与这种疾病的发病机制有关。 我们假设,CGD患者,他们的吞噬细胞和其他细胞的活性氧产生不足,可能是保护发展动脉粥样硬化。 本研究的主要终点是通过CT、MRI和其他成像方法评估这些和其他先天性免疫功能障碍患者颈动脉和冠状动脉中的动脉粥样硬化斑块形成/钙沉积。 我们发现CGD患者的颈动脉血管壁体积(动脉粥样硬化的临床前测量)显著小于年龄和性别匹配的对照组。 这一发现发表在Circulation(Sibley et al.)上。 我们继续研究该方案的患者,并将重点放在X连锁CGD携带者身上,理由是这些健康个体的ROS含量应该低于正常水平,这可能对这个年龄稍大的受试者队列具有保护作用。 目前的努力将证明这一假设,即较低水平的ROS产生是保护性的,尽管X连锁CGD携带者的情况与CGD患者不同,因为一些细胞是正常的,一些是异常的。 与此同时,我们正在与国家转化科学推进中心(NCATS)合作,涉及NADPH氧化酶活性的高通量测定的开发,以允许大规模筛选NOX 2的化学抑制剂。 (4)在正常的PMN中,NOX 2的激活导致NADPH的快速(在数秒至数分钟内)消耗和缺氧。 考虑到氧和NAPDH在代谢中的核心作用,我们在一项初步研究中比较了NOX 2激活前后PMN的代谢组,发现了PMN代谢的意外改变。 我们在CGD患者的PMN中重复这些研究,以确定ROS在这些过程中的确切作用。

项目成果

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JOHN I GALLIN其他文献

JOHN I GALLIN的其他文献

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{{ truncateString('JOHN I GALLIN', 18)}}的其他基金

Clinical Studies Of Abnormal Host Defense
宿主防御异常的临床研究
  • 批准号:
    7964198
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Effect Of Cytokines In Host Defense And Inflammation
细胞因子在宿主防御和炎症中的作用
  • 批准号:
    7964281
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Effect Of Cytokines In Host Defense And Inflammation
细胞因子在宿主防御和炎症中的作用
  • 批准号:
    8555770
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Clinical Studies Of Abnormal Host Defense
宿主防御异常的临床研究
  • 批准号:
    10014010
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Effect Of Cytokines In Host Defense And Inflammation
细胞因子在宿主防御和炎症中的作用
  • 批准号:
    7299946
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Clinical Studies Of Abnormal Host Defense
宿主防御异常的临床研究
  • 批准号:
    10272012
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Effect Of Cytokines In Host Defense And Inflammation
细胞因子在宿主防御和炎症中的作用
  • 批准号:
    7192860
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Clinical Studies Of Abnormal Host Defense
宿主防御异常的临床研究
  • 批准号:
    6984867
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Effect Of Cytokines In Host Defense And Inflammation
细胞因子在宿主防御和炎症中的作用
  • 批准号:
    8336064
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
Effect Of Cytokines In Host Defense And Inflammation
细胞因子在宿主防御和炎症中的作用
  • 批准号:
    8745306
  • 财政年份:
  • 资助金额:
    $ 21.55万
  • 项目类别:
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