A CD8+ T cell Diagnostic to Identify Children with Pulmonary Tuberculosis

CD8 T 细胞诊断可识别患有肺结核的儿童

• 批准号: 8233301
• 负责人: Deborah A. Lewinsohn
• 金额: $ 15.72万
• 依托单位: VITI, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233301
• 关键词: 5 year old; Accounting; Acid Fast Bacillae Staining Method; Adult; Affinity; Age-Years; Antigens; Automobile Driving; Bacillus (bacterium); Binding; Bioinformatics; Biological Assay; Blood; Blood Tests; CD8 Antigens; CD8B1 gene; Cells; Child; Childhood; Clinical; Collaborations; Country; Data; Detection; Diagnosis; Diagnostic; Disease; Epitopes; Equilibrium; Evaluation; Exposure to; Future; Government; HLA Antigens; Health; Human; Immunodominant Antigens; Immunological Diagnosis; Immunology; Individual; Infection; Interferons; Lead; Length; Licensing; Meningeal Tuberculosis; Morbidity - disease rate; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Patients; Peptides; Performance; Persons; Phase; Pneumonia; Process; Pulmonary Tuberculosis; Research; Risk; Sensitivity and Specificity; Small Business Innovation Research Grant; Specificity; T cell response; T-Lymphocyte; Testing; Tuberculosis; Uganda; United States National Institutes of Health; Universities; Work; abstracting; age group; base; design; immunogenic; improved; innovation; insight; mortality; novel; performance tests; programs; validation studies

DESCRIPTION (provided by applicant): Tuberculosis (TB) disease, which results from infection with Mycobacterium tuberculosis (Mtb), is a leading cause of infectious morbidity and mortality in children < 5 years old worldwide. In TB endemic regions, in which the vast majority of the world's annual 9 million adult cases of TB disease reside, children < 5 years old account for 30-40% of the total patients and those children who are infected tend to have more severe, often fatal forms of TB. A significant contributor to the deadliness of TB in children < 5 years old is the poor performance of standard TB diagnostics in this age group, especially as compared to adults. Poor diagnostics result in delayed and missed diagnoses, which in turn lead to increased morbidity and mortality in children. Currently, what is needed is a simple, robust immunodiagnostic test that will differentiate childhood pulmonary TB from non-TB pneumonia. We hypothesize that the detection of CD8+ T cells directed toward Mtb peptides can be utilized to distinguish young children with TB pneumonia from those with non-TB pneumonia. In this regard, CD8+ T cells preferentially recognize heavily Mtb-infected cells and we have observed in Ugandan children < 5 years old, that Mtb-reactive CD8+ T cells are detected in children with TB and not detected in asymptomatic children with Mtb infection/exposure. Taken together, these data suggest that CD8+ T cells correlate with bacterial burden. In parallel, we have defined 45 immunodominant, clinically- validated CD8 TB antigens through our large scale antigen discovery program that are exclusively licensed to ViTi, Inc. from OHSU. To develop an improved, broadly recognized diagnostic, we plan to use a bioinformatic approach to define peptides within these 45 immunodominant CD8 antigens likely to contain clusters of immunogenic epitopes. These peptides will be screened individually for recognition by CD8+ T cells from ethnically diverse adults with latent TB infection (LTBI) or uninfected adults. In an iterative process, we will select sets of peptides to comprise three peptide pools; one optimized for sensitivity, one for specificity, and one for a balance of sensitivity and specificity for Mtb infection. For a future Phase II SBIR application, these three peptide pools will be evaluated as an immunodiagnostic for TB pneumonia in children in a study comparing CD8+ T cell responses of Ugandan and Vietnamese children with TB pneumonia to those with non- TB pneumonia. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality in children worldwide. Young children are more likely to develop severe disease from the causative agent Mycobacterium tuberculosis (Mtb). Moreover, childhood TB pneumonia is difficult to diagnose resulting in delayed and missed diagnoses, further contributing to morbidity and mortality. The purpose of these studies is to develop a simple, robust immunodiagnostic test that distinguishes TB pneumonia from non-TB pneumonia in young children.

描述（由申请人提供）： 结核病 (TB) 是由结核分枝杆菌 (Mtb) 感染引起的，是全世界 5 岁以下儿童感染发病和死亡的主要原因。在结核病流行地区，全世界每年900万成人结核病病例中的绝大多数都居住在这些地区，5岁以下的儿童占患者总数的30-40%，而那些被感染的儿童往往病情更为严重，通常是致命的结核病。导致 5 岁以下儿童结核病致命的一个重要原因是该年龄组的标准结核病诊断效果不佳，特别是与成人相比。诊断不良会导致延误和漏诊，进而导致儿童发病率和死亡率增加。目前，我们需要一种简单、强大的免疫诊断测试来区分儿童肺结核和非结核性肺炎。我们假设检测针对 Mtb 肽的 CD8+ T 细胞可用于区分患有结核性肺炎的幼儿与非结核性肺炎。在这方面，CD8+ T 细胞优先识别严重 Mtb 感染的细胞，我们在乌干达 < 5 岁儿童中观察到，在结核病儿童中检测到 Mtb 反应性 CD8+ T 细胞，而在 Mtb 感染/暴露的无症状儿童中未检测到。 。总而言之，这些数据表明 CD8+ T 细胞与细菌负荷相关。与此同时，我们通过大规模抗原发现计划定义了 45 种免疫显性、经临床验证的 CD8 TB 抗原，这些抗原由 OHSU 独家授权给 ViTi, Inc.。为了开发一种改进的、广泛认可的诊断方法，我们计划使用生物信息学方法来定义这 45 种免疫显性 CD8 抗原中可能包含免疫原性表位簇的肽。这些肽将被单独筛选，以供来自不同种族的潜伏性结核感染 (LTBI) 或未感染成人的 CD8+ T 细胞识别。在迭代过程中，我们将选择一组肽来组成三个肽池；一种针对敏感性进行优化，一种针对特异性进行优化，另一种针对 Mtb 感染的敏感性和特异性进行平衡。对于未来的 II 期 SBIR 应用，这三个肽库将在一项比较乌干达和越南结核性肺炎儿童与非结核性肺炎儿童的 CD8+ T 细胞反应的研究中作为儿童结核性肺炎的免疫诊断进行评估。 公共卫生相关性：结核病 (TB) 是全世界儿童感染发病和死亡的最重要原因之一。幼儿更有可能因病原体结核分枝杆菌 (Mtb) 而患上严重疾病。此外，儿童结核性肺炎难以诊断，导致延误和漏诊，进一步增加发病率和死亡率。这些研究的目的是开发一种简单、可靠的免疫诊断测试，以区分幼儿的结核性肺炎和非结核性肺炎。