IMmune-mediated Adverse drug Reactions In African HIV endemic setting (IMARI-SA study)

非洲艾滋病毒流行环境中免疫介导的药物不良反应（IMARI-SA 研究）

• 批准号: 10473007
• 负责人: Jonathan Peter
• 金额: $ 8.1万
• 依托单位: UNIVERSITY OF CAPE TOWN LUNG INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-16 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473007
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Adverse reactions; Affect; Africa; Africa South of the Sahara; African; Alleles; Antigens; Antitubercular Agents; Area; Biological Assay; Biology; Biopsy Specimen; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Carbamazepine; Cells; Cessation of life; Clinical; Clinical Research; Cluster Analysis; Complex; Cutaneous; Data; Development; Disease; Drug Controls; Drug Exposure; Drug Hypersensitivity; Drug Kinetics; Drug Targeting; Drug usage; Early Diagnosis; Early treatment; Economic Burden; Epidemiology; Etiology; Flow Cytometry; Genetic; Genetic Polymorphism; Genomics; Goals; HIV; HIV Infections; HIV/TB; Health Care Costs; High Prevalence; Histocompatibility Antigens Class I; Histopathology; Hospitalization; Human; Hypersensitivity; Immune; Immunohistochemistry; Immunologics; Immunology; Individual; Laboratories; Lead; Link; Mediating; Mentorship; Molecular; Molecular Immunology; Morbidity - disease rate; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Pharmacotherapy; Phase; Phenotype; Population; Prevention; Reaction; Recovery; Research; Resolution; Resources; Risk; Risk Factors; Science; Signal Transduction; Site; Skin; Source; South Africa; Stevens-Johnson Syndrome; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; Technical Expertise; Techniques; Testing; Therapeutic; Time; Tissues; Toxic Epidermal Necrolysis; Training; Translating; Translations; Tuberculosis; abacavir; adverse drug reaction; antiretroviral therapy; burden of illness; clinical phenotype; co-infection; cohort; comorbidity; drug metabolism; epidemiology study; follow-up; genetic risk factor; immune activation; immune reconstitution; immunoglobulin receptor; in vivo; innovation; mortality; novel; peripheral blood; predictive marker; programs; response; risk variant; screening; skills; success; targeted treatment; tool; transcriptome sequencing; treatment optimization; tuberculosis treatment; whole genome

Project summary/abstract South Africa has approximately 7 million persons with HIV and 300 000 new TB cases a year, and disease treatment is complex, requiring prolonged multi-drug therapy. Cutaneous IM-ADRs occur in ~20% of all HIV-infected patients, and treatment-limiting severe cutaneous adverse drug reactions (SCAR) are both overrepresented and under-studied in Africa. The primary scientific objective of this K43 is to develop a well-defined cohort with specific clinical and immune phenotypes to define the genetic and mechanistic basis of SCAR associated with treatment of high burden diseases such as HIV and its co-morbidities including tuberculosis. The overall training objective of this K43 is to obtain theoretical and technical skills in advanced laboratory immunology that will prepare the PI to become a global leader in drug hypersensitivity science. Focal areas for mentorship and training include: i) Ex vivo assays to define drug-specific responses from peripheral blood ii) HLA-biology to identify risk allele(s), including cluster analysis, iii) Pharmaco- kinetics and genomics of culprit drug exposure and metabolism, and iv) Single cell T-cell receptor and RNA sequencing techniques, both bench and analysis components. Training areas are linked to the three study aims. Aim 1 is to define the unique clinical and immunological phenotypes of SCAR in HIV uninfected, HIV infected and TB patients with HIV co-infection in South Africa. A total of 250 SCAR cases and 500 matched controls to target drugs will be characterized using clinical tools, in vivo and drug provocation testing; and ex vivo assays such as ELISpot and flow cytometry to identify drug-specific T-cell responses. Aim 2 is to define pharmacogenomic risk factors in this cohort through high resolution HLA-typing and advanced genetic and pharmacological analyses, In Aim 3, we will investigate the hypothesis that a dominant or oligoclonal drug-specific T cell population (CD3+) exists at the site of acute tissue damage of these SCARs. We will use single cell TCR sequencing and RNAseq of activated and antigen driven CD8+ and/or CD4+ T cells from the skin in acute and recovery phases of SCAR. We will assemble a well-defined cohort of SCAR patients and controls and predict that we will define critical aspects of the epidemiology, pharmacogenomic and mechanistic basis of SCAR in high burden HIV and TB populations in Africa. This will have direct translation to SCAR in diverse treatment settings and translate into new ways to optimize treatment and prevention of SCAR in HIV-TB infected patients.

项目摘要/摘要 南非有大约700万艾滋病毒和300 000新的结核病患者 年份，疾病治疗很复杂，需要长时间的多药治疗。皮肤 IM-ADR发生在所有HIV感染的患者中约20％，并且限制治疗严重皮肤 在非洲，不良药物反应（SCAR）既代表性过多又涉及不足。 该K43的主要科学目标是开发一个定义明确的队列 使用特定的临床和免疫表型来定义遗传和机械 与艾滋病毒等高负担疾病的治疗相关的疤痕基础 合并症，包括结核病。该K43的总体培训目标是 在高级实验室免疫学中获得理论和技术技能，以准备 PI成为药物超敏反应科学的全球领导者。指导领域 培训包括：i）离体分析以定义外围药物特异性反应 血液II）HLA生物学确定风险等位基因，包括聚类分析，iii）药物 罪魁祸首和代谢的动力学和基因组学，以及iv）单细胞T细胞 受体和RNA测序技术，包括基准和分析成分。训练 区域与三个研究目的有关。目标1是定义独特的临床和 HIV未感染，HIV感染和结核病患者的疤痕的免疫学表型 艾滋病毒在南非共同感染。共有250个疤痕案件和500个匹配的对照 目标药物将使用临床工具，体内和药物挑衅测试来表征； 和体内测定，例如ELISPOT和流式细胞术，以鉴定药物特异性T细胞 回答。 AIM 2是通过高位定义该队列中的药物基因组危险因素 解决方案HLA型和先进的遗传和药理分析，在AIM 3中，我们 将研究以下假设：显性或寡克隆药物特异性T细胞种群 （CD3+）存在于这些疤痕的急性组织损伤部位。我们将使用单个单元格 激活和抗原驱动的CD8+和/或CD4+ T细胞的TCR测序和RNASEQ 疤痕的急性和恢复阶段的皮肤。 我们将组装一个明确的疤痕患者和对照组，并预测 我们将定义流行病学，药物基因组和机械学的关键方面 非洲高负担艾滋病毒和结核病种群的疤痕基础。这将有直接 在各种治疗环境中转化为疤痕，并转化为新的方式来优化 HIV-TB感染患者的治疗和预防疤痕。