Immunodiagnosis of Active Tuberculosis in HIV-infected Patients

描述（由申请人提供）：这是加州大学弗朗西斯科分校肺病学家Adithya Cattamanchi博士的K23奖申请。该K23奖将为Cattamanchi博士提供必要的支持，以实现以下目标：（1）发展以结核病（TB）为重点的独立的以患者为中心的转化研究事业;（2）在国际环境中进行结核病免疫诊断测试的临床研究;（3）在临床研究中实施先进的生物统计学方法;（4）在临床研究中实施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，Cattamanchi博士组建了一个指导团队，由主要导师菲利普霍普韦尔博士和三位共同导师组成：劳伦斯黄博士，他进行艾滋病毒肺部并发症的临床研究;丹尼斯奥斯蒙德博士，研究设计和当前最先进的生物统计分析专家;和应用T细胞免疫学专家Huyen Cao博士。Cattamanchi博士的研究将集中在基于肺的方法来免疫诊断活动性结核病。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细胞因子反应可能有助于监测对结核病的反应治疗。本研究将招募一个大型HIV感染的肺结核疑似患者队列，以实现以下特定目标：（1）比较痰涂片镜检阴性的HIV感染患者中局部和外周T细胞干扰素-γ释放试验应答诊断肺结核的性能;（2）确定M. HIV感染的活动性肺结核患者在结核治疗过程中结核特异性T细胞细胞因子谱参与者将从一个单独的，NHLBI资助的研究艾滋病毒感染者在乌干达坎帕拉肺炎的原因。将使用外周血、BAL液和口腔清洗液标本测量T细胞细胞因子应答，并储存用于未来的免疫学分析。这一建议与NHLBI的使命一致，即研究HIV相关肺部感染的肺部免疫反应。这项研究可能会导致新的和改进的方法来诊断和治疗撒哈拉以南非洲和世界其他地区的活动性结核病。相关性（参见说明）：这项研究可能会导致新的和改进的方法来诊断和治疗撒哈拉以南非洲和世界其他地区的活动性结核病。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，使它们在急需的床边可用。 (End摘要）

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)