HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin

Wuillemin, Natascha; Adam, Jacqueline; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner J; Yerly, Daniel (2013). HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin. Journal of immunology, 190(10), pp. 4956-64. Bethesda, Md.: American Association of Immunologists 10.4049/jimmunol.1202949

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Drug-induced liver injury (DILI) is a main cause of drug withdrawal. A particularly interesting example is flucloxacillin (FLUX)-DILI, which is associated with the HLA-B*57:01 allele. At present, the mechanism of FLUX-DILI is not understood, but the HLA association suggests a role for activated T cells in the pathomechanism of liver damage. To understand the interaction among FLUX, HLA molecules, and T cells, we generated FLUX-reacting T cells from FLUX-naive HLA-B*57:01(+) and HLA-B*57:01(-) healthy donors and investigated the mechanism of T cell stimulation. We found that FLUX stimulates CD8(+) T cells in two distinct manners. On one hand, FLUX was stably presented on various HLA molecules, resistant to extensive washing and dependent on proteasomal processing, suggesting a hapten mechanism. On the other hand, in HLA-B*57:01(+) individuals, we observed a pharmacological interaction with immune receptors (p-i)-based T cell reactivity. FLUX was presented in a labile manner that was further characterized by independence of proteasomal processing and immediate T cell clone activation upon stimulation with FLUX in solution. This p-i-based T cell stimulation was restricted to the HLA-B*57:01 allele. We conclude that the presence of HLA-B*57:01 drives CD8(+) T cell responses to the penicillin-derivative FLUX toward nonhapten mechanism.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Krähenbühl, Stephan

ISSN:

0022-1767

Publisher:

American Association of Immunologists

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:42

Last Modified:

17 Mar 2015 21:39

Publisher DOI:

10.4049/jimmunol.1202949

PubMed ID:

23596311

Web of Science ID:

000318546700006

URI:

https://boris.unibe.ch/id/eprint/17495 (FactScience: 225277)

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