Mechanisms of risk for sulfoniamide hypersensitivity

磺酰胺过敏的风险机制

• 批准号: 8321113
• 负责人: LAUREN A TREPANIER
• 金额: $ 28.6万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321113
• 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; 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. PUBLIC HEALTH RELEVANCE: The potentiated sulfonamide antimicrobial, sulfamethoxazole with trimethoprim, is one of the most common causes of drug hypersensitivity reactions, to include fever and pruritic skin rash. Idiosyncratic sulfonamide drug hypersensitivity reactions are difficult to predict, but appear to have a genetic predisposition in the general population, with a acquired risk that is much higher in HIV-infected patients. The overall goals of the proposed studies are to identify genetic risk factors for sulfonamide hypersensitivity in the general population, and to characterize the reasons for the high incidence of these reactions in HIV-infected patients, so that we can develop better ways to predict and prevent these adverse drug reactions. !

描述（由申请人提供）：“磺酰胺超敏反应的风险机制”超敏反应（HS）对增强的磺胺酰胺抗生素是最常见的特质不良药物反应之一，影响了约3％的一般人群，最多可影响HIV感染的患者50-60％。磺胺甲恶唑（SMX）与甲氧苄啶（TMP）结合使用，可导致发烧，皮疹和多器官毒性，是威胁生命的主要原因 人类患者的狂风爆发。需要更好地了解免疫能力和HIV感染患者的风险机制，以更好地预测和预防这些反应。鉴于免疫功能低下的患者在预防这些抗菌剂中的广泛使用以及它们对耐甲氧西林耐药的葡萄球菌的更新使用，这一点尤其重要。金黄色的感染。 特定的目标1A将专注于免疫能力患者的磺酰胺HS的遗传风险，这种患者使用具有耐受性患者作为对照的两阶段GWAS设计似乎是家族性的。特定的目标1B将集中于观察到，与药物耐受性患者相比，HS患者的外周血单核白细胞（PBMC）更容易受到磺酰胺代谢产物的毒性。了解该替代标记物的机制可能会洞悉系统性药物超敏反应的风险机制。该Subaim将通过精心表型的磺胺酰胺HS与耐受患者的PBMC中差异表达的转录本，并通过确定敲低或过表达对糖细胞中磺诺酰胺的细胞毒性的影响来确认候选转录物的机械意义。总之，这些研究将表征磺酰胺HS患者在基因组和转录水平上的遗传风险。 在AIM 2中，我们将使用Rhesus Macaques中的SIV感染模型探索HIV感染中磺酰胺HS的获得的危险因素。基线数据，包括抗氧化剂和细胞因子谱，体外细胞毒性测定以及肝脏和白细胞表达 将获得特征，然后口服口服TMP-SMX的治疗剂量。主要结果将包括血清药物加合物，药物特异性T细胞的发展以及与磺酰胺HS一致的毒理学体征，以及这些结果的基线预测指标。 这些目的的目的是更好地了解磺酰胺药物超敏反应的遗传和获得的危险因素，以便可以开发出更好的预测性和预防措施。最终目标是提高这种廉价的抗菌剂对普通人群和HIV感染患者的安全性。 公共卫生相关性：增强的磺酰胺抗菌剂，磺胺甲恶唑与甲氧苄啶，是药物超敏反应的最常见原因之一，包括发烧和核皮疹。特质的磺酰胺药物过敏反应是 难以预测，但似乎在普通人群中具有遗传易感性，而受HIV感染的患者的获得风险要高得多。拟议研究的总体目标是确定普通人群中磺酰胺超敏反应的遗传危险因素，并表征感染HIV感染的患者这些反应高发病率的原因，以便我们可以开发更好的方法来预测和防止这些不良药物反应。呢