Abstract |
A number of serious adverse drug reactions are caused by T cells. An association with HLA alleles has been identified with certain reactions, which makes it difficult to develop standardized preclinical tests to predict chemical liability. We have recently developed a T cell priming assay using the drug metabolite nitroso sulfamethoxazole (SMX-NO). We now report on reproducibility of the assay, establishment of a biobank of PBMC from 1000 HLA-typed volunteers, and generation of antigen-specific responses to a panel of compounds. Forty T cell priming assays were performed with SMX-NO; 5 gave weak responses (1.5-1.9) and 34 showed good (SI 2.0-3.9) or strong responses (SI > 4.0) using readouts for proliferation and cytokine release. Thus, SMX-NO can be used as a model reagent for in vitro T cell activation. Good to strong responses were also generated to haptenic compounds ( amoxicillin, piperacillin and Bandrowski's base) that are not associated with an HLA risk allele. Furthermore, responses were detected to carbamazepine (in HLA-B*15:02 donors), flucloxacillin (in 1 HLA-B*57:01 donor) and oxypurinol (in HLA-B*58:01 donors), which are associated with HLA-class I-restricted forms of hypersensitivity. In contrast, naïve T cell priming to ximelagatran, lumiracoxib, and lapatinib (HLA-class II-restricted forms of hypersensitivity) yielded negative results. Abacavir, which activates memory T cells in patients, did not activate naïve T cells from HLA-B*57:01 donors. This work shows that the priming assay can be used to assess primary T cell responses to drugs and to study mechanisms T cell priming for drugs that display HLA class I restriction. Additional studies are required to investigate HLA-class II-restricted reactions.
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Authors | Lee Faulkner, Andrew Gibson, Andrew Sullivan, Arun Tailor, Toru Usui, Ana Alfirevic, Munir Pirmohamed, Dean J Naisbitt, B Kevin Park |
Journal | Toxicological sciences : an official journal of the Society of Toxicology
(Toxicol Sci)
Vol. 154
Issue 2
Pg. 416-429
(12 2016)
ISSN: 1096-0929 [Electronic] United States |
PMID | 27637899
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected]. |
Chemical References |
- Cytokines
- HLA Antigens
- 4-nitrososulfamethoxazole
- Sulfamethoxazole
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Topics |
- Adult
- Biological Specimen Banks
- Cell Proliferation
(drug effects)
- Cells, Cultured
- Coculture Techniques
- Cytokines
(metabolism)
- Drug Hypersensitivity
(immunology, metabolism)
- Female
- Gene Frequency
- HLA Antigens
(genetics, immunology)
- Histocompatibility Testing
- Humans
- Leukocytes, Mononuclear
(drug effects, immunology, metabolism)
- Lymphocyte Activation
(drug effects)
- Male
- Risk Assessment
- Sulfamethoxazole
(analogs & derivatives, toxicity)
- T-Lymphocytes
(drug effects, immunology, metabolism)
- Toxicity Tests
(methods)
- Young Adult
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