Diagnostic Tests and Immunotherapy of Sarcoidosis Using Mycobacterial Proteins

使用分枝杆菌蛋白进行结节病的诊断测试和免疫治疗

基本信息

  • 批准号:
    8259724
  • 负责人:
  • 金额:
    $ 49.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-05-01 至 2014-10-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Sarcoidosis is a multisystem granulomatous disorder that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. With an incidence of -10-40 per 100,000 people, predominant in African Americans and women in the U.S., sarcoidosis represents a significant health problem and health disparity concern. The pathologic hallmark of sarcoidosis is non-caseating granulomatous inflammation. There are no diagnostic tests for sarcoidosis except for biopsy of affected tissues that carry considerable expense and risk. Sarcoidosis is widely believed to be underdiagnosed, in part due to a lack of diagnostic tools. There are no safe, effective treatments for sarcoidosis. The goals of this application are first to develop a safe, standardized diagnostic skin test for sarcoidosis, and second, to establish an immunotherapeutic approach for treatment of sarcoidosis. Our specific approach capitalizes on our recent discovery that IVIycobacterium tuberculosis catalase-peroxidase (mKatG) is a prototypic pathogenic tissue antigen in sarcoidosis. This discovery was based on a novel proteomic approach in which mKatG was isolated based on the biophysical properties of the Kveim reaction, an established diagnostic skin test for sarcoidosis which was discontinued for safety concerns since it uses allogeneic sarcoidosis tissues. Our hypotheses are 1. mKatG induces a local granulomatous response in the skin of sarcoidosis patients characteristic of disease related granulomas and Kveim reactions that can serve as a diagnostic tool, and 2. oral vaccination with mKatG suppresses experimental mKatG driven granulomatous lung inflammation in a preclinical model of sarcoidosis. In Aim 1 studies, we will manufacture recombinant mKatG under Good Manufacturing Practices suitable for use as an intradermal skin test reagent and test the safety and effect of intradermal administration in sarcoidosis patients and control subjects. In Aim 2 studies, we will test the hypothesis that oral vaccination with mKatG suppresses experimental granulomatous lung inflammation by upregulating mKatG specific regulatory T cells, thereby establishing the immunologic framework for treating sarcoidosis with oral vaccines using prototypic pathogenic antigens such as mKatG. RELEVANCE (See instructions): Our proposed studies may lead to the development of a safe, simple diagnostic skin test for sarcoidosis that could reduce risk, health care expenses and misdiagnosis. Furthermore, our studies would test whether an oral vaccine based on disease-related microbial proteins is able to suppress the characteristic inflammation seen in sarcoidosis, offering a novel, and possibly, far safer treatment strategy for sarcoidosis.
描述(申请人提供):结节病是一种多系统肉芽肿性疾病,90%以上的受影响个体累及肺部,可能导致终末期肺纤维化和死亡。发病率为每100,000人-10-40人,主要发生在非洲裔美国人和美国妇女中,结节病是一个重要的健康问题和健康差异问题。结节病的病理特征是非干酪化性肉芽肿性炎症。结节病没有诊断试验,除了对受影响的组织进行活检,这需要相当大的费用和风险。结节病被广泛认为是诊断不足,部分原因是缺乏诊断工具。结节病没有安全有效的治疗方法。本申请的目的首先是开发一种安全、标准化的结节病诊断皮肤试验,其次是建立一种治疗结节病的免疫学方法。我们的具体方法利用了我们最近的发现,即结核分枝杆菌过氧化氢酶-过氧化物酶(mKatG)是结节病中的原型致病组织抗原。这一发现是基于一种新的蛋白质组学方法,其中mKatG是基于Kveim反应的生物物理特性分离的,Kveim反应是一种已建立的结节病诊断皮肤试验,由于其使用同种异体结节病组织,因此出于安全性考虑而停止。我们的假设是1。mKatG在结节病患者的皮肤中诱导局部肉芽肿反应,其特征在于疾病相关的肉芽肿和Kveim反应,其可以用作诊断工具,以及2.在结节病的临床前模型中口服mKatG疫苗抑制实验性mKatG驱动的肉芽肿性肺炎。在目标1研究中,我们将根据药品生产质量管理规范生产适合用作皮内皮试试剂的重组mKatG,并检测结节病患者和对照受试者皮内给药的安全性和有效性。在目标2研究中,我们将检验mKatG口服疫苗通过上调mKatG特异性调节性T细胞抑制实验性肉芽肿性肺部炎症的假设,从而建立使用原型致病性抗原(如mKatG)口服疫苗治疗结节病的免疫学框架。相关性(参见说明):我们提出的研究可能会导致开发一种安全,简单的结节病诊断皮肤试验,可以减少风险,医疗保健费用和误诊。此外,我们的研究将测试基于疾病相关微生物蛋白的口服疫苗是否能够抑制结节病中观察到的特征性炎症,为结节病提供一种新的,可能更安全的治疗策略。

项目成果

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David R Moller其他文献

David R Moller的其他文献

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{{ truncateString('David R Moller', 18)}}的其他基金

GRADS Cooperative Research Project: JHU Clinical Center
GRADS 合作研究项目:JHU 临床中心
  • 批准号:
    8464252
  • 财政年份:
    2012
  • 资助金额:
    $ 49.2万
  • 项目类别:
GRADS Cooperative Research Project: JHU Clinical Center
GRADS 合作研究项目:JHU 临床中心
  • 批准号:
    8265092
  • 财政年份:
    2012
  • 资助金额:
    $ 49.2万
  • 项目类别:
GRADS Cooperative Research Project: JHU Clinical Center
GRADS 合作研究项目:JHU 临床中心
  • 批准号:
    8662311
  • 财政年份:
    2012
  • 资助金额:
    $ 49.2万
  • 项目类别:
Diagnostic Tests and Immunotherapy of Sarcoidosis Using Mycobacterial Proteins
使用分枝杆菌蛋白进行结节病的诊断测试和免疫治疗
  • 批准号:
    8073716
  • 财政年份:
    2011
  • 资助金额:
    $ 49.2万
  • 项目类别:
Pathogenic Mycobacterial Proteins in Sarcoidosis
结节病中的致病性分枝杆菌蛋白
  • 批准号:
    7415235
  • 财政年份:
    2006
  • 资助金额:
    $ 49.2万
  • 项目类别:
Pathogenic Mycobacterial Proteins in Sarcoidosis
结节病中的致病性分枝杆菌蛋白
  • 批准号:
    7615024
  • 财政年份:
    2006
  • 资助金额:
    $ 49.2万
  • 项目类别:
Pathogenic Mycobacterial Proteins in Sarcoidosis
结节病中的致病性分枝杆菌蛋白
  • 批准号:
    7069230
  • 财政年份:
    2006
  • 资助金额:
    $ 49.2万
  • 项目类别:
Pathogenic Mycobacterial Proteins in Sarcoidosis
结节病中的致病性分枝杆菌蛋白
  • 批准号:
    7231987
  • 财政年份:
    2006
  • 资助金额:
    $ 49.2万
  • 项目类别:
Amyloid Precursor Proteins in Sarcoidosis
结节病中的淀粉样前体蛋白
  • 批准号:
    6819461
  • 财政年份:
    2004
  • 资助金额:
    $ 49.2万
  • 项目类别:
Amyloid Precursor Proteins in Sarcoidosis
结节病中的淀粉样前体蛋白
  • 批准号:
    6920606
  • 财政年份:
    2004
  • 资助金额:
    $ 49.2万
  • 项目类别:

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