药物超敏反应安全评价体外替代方法的研究进展

超敏反应是药物的严重不良反应之一,严重时可危及患者生命。目前超敏反应(Ⅰ,Ⅳ型)临床前评价方法多为整体动物实验方法,基于动物福利和3R原则的考虑,以及体外替代方法的迅速发展,目前已建立了数种药物致敏性评价的体外替代方法,包括根据肥大细胞和嗜碱性粒细胞在Ⅰ型超敏反应中发挥的关键作用,用实验室易获得的肥大细胞和嗜碱性粒细胞系如RBL-2H3和KU812研究药物的Ⅰ型超敏反应,另外鉴于树突状细胞在Ⅳ型超敏反应中抗原呈递作用,用THP-1细胞构建的h-CLAT试验体系和LC-SA试验体系在皮肤致敏性的评价方面都显示出较好的发展前景。本文综合近年的国内外文献,对超敏反应的体外替代方法进行了综合论述和评估。     

Hypersensitivity reactions to anti-SARS-CoV-2 vaccines: Basophil reactivity to excipients

Basophil activation test (BAT) can tackle multiple mechanisms underlying acute and delayed hypersensitivity to drugs and vaccines and might complement conventional allergy diagnostics but its role in anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-related hypersensitivity is ill-defined. Therefore, 89 patients with possible hypersensitivity (56 % with delayed mucocutaneous manifestations) to anti-SARS-CoV-2 vaccines were tested with BAT for Macrogol 3350, DMG-PEG 2000, PEG 20000, polysorbate-80 and trometamol and compared to 156 subjects undergoing pre-vaccine BAT. A positive BAT was associated with delayed reaction onset (p = 0.010) and resolution (p = 0.011). BAT was more frequently positive to DMG-PEG 2000 than to other excipients in both groups (p < 0.001). DMG-PEG 2000 reactivity was less frequent in vaccine-naïve (6 %) than vaccinated subjects (35 %, p < 0.001) and associated with mRNA-1273 vaccination. DMG-PEG 2000 BAT might therefore have a diagnostic role in subjects with delayed hypersensitivity reactions. Natural immunity might be a key player in basophil activation.     

Efficacy and safety of omalizumab in adult patients with wheat-dependent exercise-induced anaphylaxis: Reduction of in vitro basophil activation and allergic reaction to wheat

BackgroundIn patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA.MethodsIn this phase 2, multicentre single-arm trial, 20 adult patients with WDEIA were enrolled (UMIN 000019250). All patients were administered 150–600 mg of omalizumab subcutaneously and evaluations (basophil activation and blood examination) were performed at regular intervals during administration period (0–48 weeks) and observation period (48–68 weeks). Primary endpoint was proportion of the patients who achieved a basophil activation rate below 10% with fractionated wheat preparations, and secondary endpoint was proportion of the patients with no allergic reactions after wheat products ingestion.ResultsDuring the omalizumab treatment, more than 80% of the patients achieved the basophil activation rate less than 10% against all fractionated wheat preparations, and 68.8% of the patients who achieved the primary endpoint experienced no allergic reaction. During the observation period, the proportion of the patients who achieved a basophil activation rate below 10% decreased gradually, and the proportion of patients with positive allergic reactions increased gradually thereafter and reached maximum of 46.7%. Severe adverse events were not observed during the study.ConclusionsLong-term omalizumab treatment is safe and effective for adult patients with WDEIA when assessed by basophil activation rate with wheat allergens as well as allergic reactions after lifting of restrictions on wheat intake. However, this is not enough to achieve desensitization.