Immunodiagnosis of Active Tuberculosis in HIV-infected Patients

描述(由申请人提供)：这是为加州大学旧金山分校的肺科医生Adithya Cattamanci博士申请K23奖项。这一K23奖项将为卡塔曼奇博士提供必要的支持，以实现以下目标：(1)发展以患者为中心的独立的结核病(TB)翻译研究生涯；(2)在国际环境下开展结核病免疫诊断试验的临床研究；(3)在临床研究中实施先进的生物统计学方法；以及(4)发展应用T细胞免疫学的理论和实践技能。为了实现这些目标，卡塔曼奇博士组建了一支由主要导师、转化型结核病研究领域的领先专家Phillip Hopewell博士和三名共同导师组成的指导团队：负责HIV肺部并发症临床调查的Laurence Huang博士、研究设计和最新生物统计分析专家Dennis Osmond博士以及应用T细胞免疫学专家Huyen Cao博士。卡塔曼奇博士的研究将集中在活动性结核病的一种基于肺部的免疫诊断方法上。这项拟议的研究将扩展最近的数据，这些数据表明：(1)局部而不是外周T细胞细胞因子反应可以更好地区分活动性结核病与LTBI和其他呼吸道感染，以及(2)T细胞细胞因子反应在监测结核病治疗的反应方面可能是有用的。这项拟议的研究将招募一大批感染艾滋病毒的肺结核病嫌疑人，以解决以下具体目标：(1)比较局部和外周T细胞干扰素-伽马释放试验对痰涂片镜检阴性的艾滋病毒感染患者诊断肺结核的表现；(2)确定在艾滋病毒感染的活动性肺结核患者的结核病治疗过程中结核分枝杆菌特异性T细胞细胞因子的特征。参与者将从另一项由NHLBI资助的关于乌干达坎帕拉艾滋病毒感染患者肺炎原因的研究中抽出。外周血液、BAL液和口腔冲洗标本将用于测量T细胞细胞因子反应，并储存用于未来的免疫学分析。这一建议与NHLBI研究HIV相关性肺部感染的肺免疫反应的使命是一致的。这项研究可能导致撒哈拉以南非洲和世界其他地区诊断和治疗活动性结核病的新的和改进的方法。相关性(见说明)：这项研究可能导致撒哈拉以南非洲和世界其他地区诊断和治疗活动性结核病的新的和改进的方法。这项研究还可能有助于确定预测结核病治疗反应的新标记物。这可能有助于加快对新药的评估，使其在急需的床边可用。(摘要结束)

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Adithya Cattamanchi, a pulmonologist at the University of California, San Francisco. This K23 award will provide Dr. Cattamanchi with the support necessary to accomplish the following goals: (1) to develop an indepenent patient-centered translational research career focused on tuberculosis (TB); (2) to conduct clinical investigations of immunodiagnostic tests for TB in an international setting; (3) to implement advanced biostatistical methods in clinical studies; and (4) to develop theoretical and practical skills in applied T-cell immunology. To achieve these goals, Dr. Cattamanchi has assembled a mentoring team comprised of a primary mentor, Dr. Phillip Hopewell, a leading expert in translational TB research, and three co-mentors: Dr. Laurence Huang, who conducts clinical investigations of the pulmonary complications of HIV; Dr. Dennis Osmond, an expert in study design and current state-of-theart biostatistical analysis; and Dr. Huyen Cao, an expert in applied T-cell immunology. Dr. Cattamanchi's research will focus on a lung-based approach to immunodiagnosis of active TB. The proposed research will expand on recent data suggesting that (1) local rather than peripheral T-cell cytokine responses can better discriminate active TB from both LTBI and other respiratory infections and (2) T-cell cytokine responses may be useful in monitoring response to TB treatment. The proposed study will enroll a large cohort of HIV-infected pulmonary TB suspects to address the following specific aims: (1) To compare the performance of local and peripheral T-cell interferon-gamma release assay responses for the diagnosis of pulmonary TB in HIV-infected patients with negative sputum smear microscopy and (2) To define the M. TB-specific T-cell cytokine profile during the course of TB treatment in HIV-infected patients with active pulmonary TB. The participants will be drawn from a separate, NHLBI-funded study of the causes of pneumonia in HIV-infected patients in Kampala, Uganda. Peripheral blood, BAL fluid, and oral wash specimens will be used to measure T-cell cytokine responses and stored for future immunologic analyses. This proposal is consistent with the NHLBI's mission to study pulmonary immune responses in HIVassociated pulmonary infections. The study may lead to new and improved approaches to diagnosing and treating active TB in sub-Saharan Africa and other parts of the world. RELEVANCE (See instructions): The study may lead to new and improved approaches to diagnosing and treating active TB in sub-Saharan Africa and other parts of the world. The study may also help identify new markers to predict response to TB therapy. This may help accelerate evaluation of new drugs, making them available at the bedside where they are urgently needed. (End of Abstract)