دورية أكاديمية
Definition of the Nature and Hapten Threshold of the β-Lactam Antigen Required for T Cell Activation In Vitro and in Patients.
| العنوان: | Definition of the Nature and Hapten Threshold of the β-Lactam Antigen Required for T Cell Activation In Vitro and in Patients. |
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| المؤلفون: | Meng X; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and., Al-Attar Z; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and., Yaseen FS; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and., Jenkins R; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and., Earnshaw C; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and., Whitaker P; Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds LS9 7TF, United Kingdom., Peckham D; Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds LS9 7TF, United Kingdom., French NS; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and., Naisbitt DJ; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and., Park BK; Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool L69 3GE, United Kingdom; and bkpark@liv.ac.uk. |
| المصدر: | Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 Jun 01; Vol. 198 (11), pp. 4217-4227. Date of Electronic Publication: 2017 Apr 24. |
| نوع المنشور: | Case Reports; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Bethesda, MD : American Association of Immunologists Original Publication: Baltimore : Williams & Wilkins, c1950- |
| مواضيع طبية MeSH: | Lymphocyte Activation*, Anti-Bacterial Agents/*immunology , CD4-Positive T-Lymphocytes/*immunology , Drug Hypersensitivity/*immunology , Epitopes/*immunology , Haptens/*immunology , beta-Lactams/*immunology, Adult ; Anti-Bacterial Agents/administration & dosage ; Anti-Bacterial Agents/pharmacology ; Antigens/immunology ; CD4-Positive T-Lymphocytes/physiology ; Epitopes/chemistry ; Female ; Haptens/administration & dosage ; Haptens/chemistry ; Haptens/metabolism ; Humans ; Immune Tolerance ; Male ; Mass Spectrometry ; Piperacillin/administration & dosage ; Piperacillin/immunology ; Piperacillin/metabolism ; Serum Albumin/chemistry ; Serum Albumin/immunology ; Young Adult ; beta-Lactams/administration & dosage ; beta-Lactams/metabolism |
| مستخلص: | Covalent modification of protein by drugs may disrupt self-tolerance, leading to lymphocyte activation. Until now, determination of the threshold required for this process has not been possible. Therefore, we performed quantitative mass spectrometric analyses to define the epitopes formed in tolerant and hypersensitive patients taking the β-lactam antibiotic piperacillin and the threshold required for T cell activation. A hydrolyzed piperacillin hapten was detected on four lysine residues of human serum albumin (HSA) isolated from tolerant patients. The level of modified Lys 541 ranged from 2.6 to 4.8%. Analysis of plasma from hypersensitive patients revealed the same pattern and levels of modification 1-10 d after the commencement of therapy. Piperacillin-responsive skin-homing CD4 + clones expressing an array of Vβ receptors were activated in a dose-, time-, and processing-dependent manner; analysis of incubation medium revealed that 2.6% of Lys 541 in HSA was modified when T cells were activated. Piperacillin-HSA conjugates that had levels and epitopes identical to those detected in patients were shown to selectively stimulate additional CD4 + clones, which expressed a more restricted Vβ repertoire. To conclude, the levels of piperacillin-HSA modification that activated T cells are equivalent to the ones formed in hypersensitive and tolerant patients, which indicates that threshold levels of drug Ag are formed in all patients. Thus, the propensity to develop hypersensitivity is dependent on other factors, such as the presence of T cells within an individual's repertoire that can be activated with the β-lactam hapten and/or an imbalance in immune regulation. (Copyright © 2017 by The American Association of Immunologists, Inc.) |
| التعليقات: | Comment in: Sci Transl Med. 2017 May 3;9(388):null. (PMID: 28469034) Erratum in: J Immunol. 2018 Feb 2;:. (PMID: 29427419) |
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| معلومات مُعتمدة: | MR/L006758/1 United Kingdom MRC_ Medical Research Council; G0700654 United Kingdom Medical Research Council |
| المشرفين على المادة: | 0 (Anti-Bacterial Agents) 0 (Antigens) 0 (Epitopes) 0 (Haptens) 0 (Serum Albumin) 0 (beta-Lactams) X00B0D5O0E (Piperacillin) |
| تواريخ الأحداث: | Date Created: 20170426 Date Completed: 20170922 Latest Revision: 20231112 |
| رمز التحديث: | 20231112 |
| مُعرف محوري في PubMed: | PMC5444528 |
| DOI: | 10.4049/jimmunol.1700209 |
| PMID: | 28438900 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1550-6606 |
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| DOI: | 10.4049/jimmunol.1700209 |