Mechanisms of risk for sulfoniamide hypersensitivity

磺酰胺过敏的风险机制

• 批准号: 8794443
• 负责人: LAUREN A TREPANIER
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794443
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Affect; Animal Model; Antibiotics; Antibodies; Antioxidants; Biological Assay; Bronchitis; Cells; Child; Clinical Markers; Cutaneous; Cystic Fibrosis; Data; Development; Drug Eruptions; Drug Hypersensitivity; Drug toxicity; Exanthema; Fever; Gene Expression; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genomics; Goals; HIV; HIV Infections; HIV-1; Hematologic Neoplasms; Hepatic; Human; Hypersensitivity; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; In Vitro; Incidence; Infection; Intervention; Knowledge; Lead; Leukocytes; Life; Light; Liver; Lymphoid Cell; Macaca mulatta; Measures; Metabolic Biotransformation; Methicillin Resistance; Modeling; Molecular Profiling; Mononuclear Leukocytes; Opportunistic Infections; Oral Administration; Organ; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pneumocystis; Pneumonia; Population; Predisposition; Prevention; Prevention strategy; Prophylactic treatment; Reaction; Research; Research Design; Resources; Retroviridae; Risk; Risk Factors; SIV; Safety; Serum; Skin; Small Interfering RNA; Staging; Stevens-Johnson Syndrome; Sulfamethoxazole; Sulfonamides; Surrogate Markers; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Toxic Epidermal Necrolysis; Toxic effect; Toxoplasmosis; Transcript; Trimethoprim; Trimethoprim-Sulfamethoxazole; Urinary tract infection; adduct; alternative treatment; antimicrobial; congenital immunodeficiency; cytokine; cytotoxicity; design; differential expression; dosage; effective therapy; efficacy testing; genetic risk factor; genome wide association study; high risk; immunogenicity; improved; insight; knock-down; methicillin resistant Staphylococcus aureus; mortality; nonhuman primate; peripheral blood; prevent; primary outcome; prospective; research study

DESCRIPTION (provided by applicant): "Mechanisms of risk for sulfonamide hypersensitivity" Hypersensitivity (HS) to potentiated sulfonamide antibiotics is one of the most common idiosyncratic adverse drug reactions, affecting about 3% of the general population, and up to 50-60% of HIV-infected patients. Sulfamethoxazole (SMX), in combination with trimethoprim (TMP), can lead to fever, skin rash and multi-organ toxicity, and is the leading cause of life-threatening bullous skin eruptions in human patients. A better understanding of the mechanisms of risk in both immunocompetent and HIV-infected patients is needed to better predict and prevent these reactions. This is particularly important in light of the widespread use of these antimicrobials fo infection prophylaxis in immunocompromised patients, as well as their renewed use for methicillin-resistant Staph. aureus infections. Specific aim 1a will focus on genetic risk of sulfonamide HS in immunocompetent patients, which appears to be familial, using a two-stage GWAS design with tolerant patients as controls. Specific aim 1b will focus on the observation that peripheral blood mononuclear leukocytes (PBMCs) from HS patients are more susceptible to toxicity from sulfonamide metabolites compared to drug tolerant patients. Understanding the mechanism(s) for this surrogate marker may provide insight into the mechanisms of risk for systemic drug hypersensitivity. This subaim will identify differentially expressed transcripts in PBMCs from carefully phenotyped sulfonamide HS versus tolerant patients, and confirm the mechanistic significance of candidate transcripts by determining the effects of knock-down or over-expression on the cytotoxicity from sulfonamide metabolites in lymphoid cells. Together, these studies will characterize genetic risk for sulfonamide HS patients on both the genomic and transcriptional levels. In Aim 2, we will explore acquired risk factors for sulfonamide HS in HIV infection, using an SIV infection model in rhesus macaques. Baseline data, to include antioxidant and cytokine profiles, in vitro cytotoxicity assays, and liver and leukocyte expression profiles, will be obtained, followed by oral administration of a therapeutic dosage of TMP-SMX. Primary outcomes will include development of serum drug adducts, drug specific T cells, and toxicologic signs consistent with sulfonamide HS, along with baseline predictors for these outcomes. The goal of these aims is to better understand the genetic and acquired risk factors for sulfonamide drug hypersensitivity, so that better predictive and preventative measures can be developed. The ultimate goal is to improve the safety of this inexpensive antimicrobial for both the general population and for HIV-infected patients.

描述（由申请人提供）：“磺胺类超敏反应的风险机制”对增效磺胺类抗生素的超敏反应（HS）是最常见的特异质药物不良反应之一，影响约3%的一般人群，高达50-60%的HIV感染患者。磺胺甲恶唑（SMX）与甲氧苄啶（TMP）合用可导致发热、皮疹和多器官毒性，是危及生命的首要原因 人类患者的大疱性皮疹。为了更好地预测和预防这些反应，需要更好地了解免疫功能正常和HIV感染患者的风险机制。这是特别重要的，因为这些抗菌剂广泛用于免疫功能低下患者的感染预防，以及它们重新用于耐甲氧西林葡萄球菌。金黄色葡萄球菌感染 具体目标1a将重点关注免疫功能正常患者中磺胺HS的遗传风险，这似乎是家族性的，使用两阶段GWAS设计，耐受患者作为对照。具体目标1b将重点关注以下观察结果：与药物耐受患者相比，HS患者的外周血单核白细胞（PBMC）对磺胺代谢物的毒性更敏感。了解这种替代标志物的机制可能有助于深入了解全身性药物超敏反应的风险机制。该子目标将鉴定来自仔细表型化的磺胺HS与耐受患者的PBMC中的差异表达的转录物，并通过确定敲低或过表达对淋巴细胞中磺胺代谢物的细胞毒性的影响来确认候选转录物的机制意义。总之，这些研究将在基因组和转录水平上表征磺胺类HS患者的遗传风险。 在目标2中，我们将使用恒河猴中的SIV感染模型，探索HIV感染中磺胺HS的获得性危险因素。基线数据，包括抗氧化剂和细胞因子特征、体外细胞毒性试验以及肝脏和白细胞表达 将获得曲线，随后口服施用治疗剂量的TMP-SMX。主要结局将包括血清药物加合物、药物特异性T细胞和与磺胺HS一致的毒理学体征的形成，沿着这些结局的基线预测因素。 这些目标的目的是更好地了解磺胺类药物超敏反应的遗传和获得性风险因素，以便制定更好的预测和预防措施。最终目标是提高这种廉价抗菌剂对普通人群和HIV感染患者的安全性。