Mechanisms of risk for sulfoniamide hypersensitivity

描述(由申请人提供)：“磺胺过敏的风险机制”对强化的磺胺类抗生素的过敏(HS)是最常见的特殊药物不良反应之一，影响大约3%的普通人群和高达50%-60%的艾滋病毒感染患者。磺胺甲恶唑(SMX)与甲氧苄啶(TMP)联合使用可导致发热、皮疹和多器官毒性，是威胁生命的主要原因 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活性患者和艾滋病毒感染患者的风险机制。这一点尤其重要，因为这些抗菌素被广泛用于免疫低下患者的感染预防，以及它们对耐甲氧西林葡萄球菌的重新使用。金黄色葡萄球菌感染。具体目标1a将重点放在免疫能力患者中磺胺HS的遗传风险，这似乎是家族性的，使用两阶段GWAS设计，以耐受性患者为对照。具体目的1b将重点观察HS患者的外周血单个核细胞(PBMC)比耐药患者更容易受到磺胺代谢产物的毒性影响。了解这种替代标志物的机制(S)可能有助于深入了解全身性药物超敏反应的风险机制。这一子目标将鉴定表型仔细的磺胺HS患者和耐受患者PBMC中差异表达的转录本，并通过确定下调或过度表达对淋巴细胞中磺胺代谢物细胞毒性的影响来确认候选转录本的机制意义。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，我们将利用恒河猴的SIV感染模型，探索磺胺HS在HIV感染中的获得性危险因素。基线数据，包括抗氧化剂和细胞因子谱，体外细胞毒性分析，以及肝脏和白细胞的表达 将获得简档，然后口服治疗剂量的TMP-SMX。主要结果将包括血清药物加合物的形成、药物特异性T细胞和与磺胺HS一致的毒理学迹象，以及这些结果的基线预测因素。这些目的是为了更好地了解磺胺类药物过敏的遗传和获得性危险因素，以便开发更好的预测性和预防性措施。最终目标是提高这种廉价抗菌剂对普通人群和艾滋病毒感染患者的安全性。

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.