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）疾病是由结核分枝杆菌（MTB）感染引起的，是全球<5岁儿童感染性发病和死亡率的主要原因。在结核病地区，世界上绝大多数900万成人结核病病例中的绝大多数居住在该地区，儿童<5岁的儿童占总患者的30-40％，而被感染的儿童往往往往具有更严重的，通常是致命的结核病形式。在5岁少于5岁的儿童中，结核病的致命性的重要原因是该年龄段的标准结核病诊断表现不佳，尤其是与成年人相比。诊断不佳导致延迟和错过的诊断，进而导致儿童发病率和死亡率增加。目前，需要的是一项简单，可靠的免疫诊断测试，它将将儿童肺结核与非TB肺炎区分开。我们假设可以利用针对MTB肽的CD8+ T细胞的检测来区分TB肺炎的幼儿和非TB肺炎患者。在这方面，CD8+ T细胞优先识别了MTB感染的细胞，并且在乌干达儿童<5岁的儿童中，MTB反应性CD8+ T细胞在TB儿童中被检测到MTB感染/暴露/暴露/暴露的儿童。综上所述，这些数据表明CD8+ T细胞与细菌负担相关。同时，我们通过大规模的抗原发现程序定义了45个免疫主导，临床验证的CD8 TB抗原，这些抗原抗原仅从OHSU获得了Viti，Inc。的许可。为了开发改进的，广泛认可的诊断，我们计划使用生物信息学方法来定义这45种免疫主导CD8抗原，可能包含免疫原性表位簇。这些肽将被单独筛选，以识别来自患有潜在TB感染（LTBI）或未感染的成年人的种族多样的成年人的CD8+ T细胞。在迭代过程中，我们将选择一组肽组成三个肽池。一种针对灵敏度优化，一种针对特异性，一种用于MTB感染的灵敏度和特异性的平衡。对于未来的II期SBIR应用，这三个肽池将被评估为儿童中TB肺炎的免疫诊断，比较了乌干达和越南TB肺炎的CD8+ T细胞反应与非TB肺炎的CD8+ T细胞反应。 公共卫生相关性：结核病（TB）是全球儿童传染病和死亡率最重要的原因之一。幼儿更有可能从结核分枝杆菌（MTB）的病因分枝杆菌中发展出严重的疾病。此外，儿童结核病肺炎很难诊断，从而导致延迟和遗漏的诊断，进一步导致发病率和死亡率。这些研究的目的是开发一种简单，可靠的免疫诊断测试，将TB肺炎与幼儿中的非TB肺炎区分开来。