Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients.
Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients.
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DOI：
10.1021/acs.chemrestox.2c00231
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发表时间：
2022-11-21
影响因子：
4.1
通讯作者：
Naisbitt, Dean John
中科院分区：
文献类型：
--
作者：
Ariza, Adriana;Jaruthamsophon, Kanoot;Meng, Xiaoli;Labella, Marina;Adair, Kareena;Tailor, Arun;Sukasem, Chonlaphat;Whitaker, Paul;Peckham, Daniel;Pirmohamed, Munir;Torres, Maria Jose;Naisbitt, Dean John
β-内酰胺酶抑制剂如克拉维酸和他唑巴坦被开发用于克服β-内酰胺抗生素耐药性。对这些药物的超敏反应尚未详细研究，激活T细胞的抗原决定簇也尚未确定。本研究的目的是（i）表征超敏患者的克拉维汀和他唑巴坦反应性T细胞，（ii）探索克拉维汀和他唑巴坦T细胞交叉反应性，（iii）确定有助于T细胞反应性的抗原决定簇。通过增殖和细胞因子释放试验评估抗原特异性、T细胞活化途径以及与克拉维素和他唑巴坦特异性T细胞克隆的交叉反应性。通过基于质谱的蛋白质组学方法分析抗原决定簇。以MHC II类限制性和剂量依赖性方式刺激克拉维素和他唑巴坦应答性CD 4 + T细胞克隆增殖和分泌IFN-γ。克拉维素和他唑巴坦的T细胞活化依赖于抗原呈递细胞，因为它们的固定阻止了T细胞应答。在克拉维霉素和他唑巴坦-T细胞之间观察到强烈的交叉反应性;然而，两种药物都不能激活β-内酰胺类抗生素反应性T细胞。质谱分析表明，这两种化合物形成多个抗原决定簇与蛋白质上的赖氨酸残基，包括重叠的醛和水合醛加合物的质量增加70和88 Da，分别。总的来说，这些数据表明，尽管克拉维汀和他唑巴坦在结构上不同，但两种药物形成的抗原决定簇重叠，这解释了观察到的T细胞交叉反应性。
β-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome β-lactam antibiotic resistance. Hypersensitivity reactions to these drugs have not been studied in detail, and the antigenic determinants that activate T-cells have not been defined. The objectives of this study were to (i) characterize clavulanate- and tazobactam-responsive T-cells from hypersensitive patients, (ii) explore clavulanate and tazobactam T-cell crossreactivity, and (iii) define the antigenic determinants that contribute to T-cell reactivity. Antigen specificity, pathways of T-cell activation, and crossreactivity with clavulanate- and tazobactam-specific T-cell clones were assessed by proliferation and cytokine release assays. Antigenic determinants were analyzed by mass spectrometry-based proteomics methods. Clavulanate- and tazobactam-responsive CD4+ T-cell clones were stimulated to proliferate and secrete IFN-γ in an MHC class II-restricted and dose-dependent manner. T-cell activation with clavulanate- and tazobactam was dependent on antigen presenting cells because their fixation prevented the T-cell response. Strong crossreactivity was observed between clavulanate- and tazobactam-T-cells; however, neither drug activated β-lactam antibiotic-responsive T-cells. Mass spectrometric analysis revealed that both compounds form multiple antigenic determinants with lysine residues on proteins, including an overlapping aldehyde and hydrated aldehyde adduct with mass additions of 70 and 88 Da, respectively. Collectively, these data show that although clavulanate and tazobactam are structurally distinct, the antigenic determinants formed by both drugs overlap, which explains the observed T-cell cross-reactivity.
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影响因子：
2.9
作者：
Kuzin, AP;Nukaga, M;Knox, JR
通讯作者：
Knox, JR
DOI：
10.1159/000233659
发表时间：
1985-01-01
期刊：
INTERNATIONAL ARCHIVES OF ALLERGY AND APPLIED IMMUNOLOGY
影响因子：
--
作者：
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Torres, Maria Jose
影响因子：
13.5
作者：
Kim, Seung-Hyun;Saide, Katy;Naisbitt, Dean J.
通讯作者：
Naisbitt, Dean J.
DOI：
10.1016/j.jaip.2020.12.051
发表时间：
2021-05-06
影响因子：
9.4
作者：
Casimir-Brown, Rosamund Sara;Kennard, Lucinda;Wagner, Annette
通讯作者：
Wagner, Annette