Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01

Yun, James Jin Sup; Marcaida, Maria J; Eriksson, Klara K; Jamin, Heidi; Fontana, Stefano; Pichler, Werner Joseph; Yerly, Daniel (2014). Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01. Journal of immunology, 192(7), pp. 2984-2993. American Association of Immunologists 10.4049/jimmunol.1302306

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Allopurinol (ALP) hypersensitivity is a major cause of severe cutaneous adverse reactions and is strongly associated with the HLA-B*58:01 allele. However, it can occur in the absence of this allele with identical clinical manifestations. The immune mechanism of ALP-induced severe cutaneous adverse reactions is poorly understood, and the T cell-reactivity pattern in patients with or without the HLA-B*58:01 allele is not known. To understand the interactions among the drug, HLA, and TCR, we generated T cell lines that react to ALP or its metabolite oxypurinol (OXP) from HLA-B*58:01(+) and HLA-B*58:01(-) donors and assessed their reactivity. ALP/OXP-specific T cells reacted immediately to the addition of the drugs and bypassed intracellular Ag processing, which is consistent with the "pharmacological interaction with immune receptors" (p-i) concept. This direct activation occurred regardless of HLA-B*58:01 status. Although most OXP-specific T cells from HLA-B*58:01(+) donors were restricted by the HLA-B*58:01 molecule for drug recognition, ALP-specific T cells also were restricted to other MHC class I molecules. This can be explained by in silico docking data that suggest that OXP binds to the peptide-binding groove of HLA-B*58:01 with higher affinity. The ensuing T cell responses elicited by ALP or OXP were not limited to particular TCR Vβ repertoires. We conclude that the drug-specific T cells are activated by OXP bound to HLA-B*58:01 through the p-i mechanism.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology

UniBE Contributor:

Yun, James Jin Sup; Pichler, Werner Joseph and Yerly, Daniel

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-1767

Publisher:

American Association of Immunologists

Language:

English

Submitter:

Stefan Kuchen

Date Deposited:

07 Apr 2015 14:00

Last Modified:

07 Apr 2015 14:00

Publisher DOI:

10.4049/jimmunol.1302306

PubMed ID:

24591375

BORIS DOI:

10.7892/boris.66389

URI:

https://boris.unibe.ch/id/eprint/66389

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