Immunodiagnosis of Active Tuberculosis in HIV-infected Patients

描述（由申请人提供）：这是一份为加州大学旧金山分校肺病学家Adithya Cattamanchi博士申请K23奖的申请。K23奖将为卡塔曼奇博士提供必要的支持，以实现以下目标：(1)发展独立的以患者为中心的结核病转化研究事业；(2)在国际范围内开展结核病免疫诊断试验的临床调查；(3)在临床研究中应用先进的生物统计学方法；(4)培养应用t细胞免疫学的理论和实践技能。为了实现这些目标，catamanchi博士组建了一个指导团队，其中包括一名主要导师、结核病转化研究的主要专家Phillip Hopewell博士和三名共同导师：对艾滋病毒肺部并发症进行临床调查的Laurence Huang博士；丹尼斯·奥斯蒙德博士是研究设计和最新生物统计分析方面的专家；以及应用t细胞免疫学专家曹焕彦博士。Cattamanchi博士的研究将集中在基于肺部的活动性结核病免疫诊断方法上。拟议的研究将扩展最近的数据，这些数据表明：(1)局部而不是周围的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；(2)t细胞细胞因子反应可能有助于监测对结核病治疗的反应。该研究将招募大量hiv感染的肺结核疑似患者，以实现以下具体目标：(1)比较痰涂片镜检阴性的hiv感染患者的局部和外周t细胞干扰素γ释放试验反应在诊断肺结核方面的表现；(2)确定hiv感染的活动性肺结核患者在结核病治疗过程中的结核分枝杆菌特异性t细胞细胞因子谱。参与者将从由nhlbi资助的一项关于乌干达坎帕拉艾滋病毒感染患者肺炎原因的单独研究中抽取。外周血、BAL液和口腔清洗标本将用于测量t细胞细胞因子反应，并储存以供将来的免疫学分析。这一建议与NHLBI研究hiv相关肺部感染的肺免疫反应的使命是一致的。这项研究可能会导致在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）：该研究可能导致在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新的标志物来预测对结核病治疗的反应。这可能有助于加速新药的评估，使它们能够在迫切需要的地方获得。（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)