Received for publication January 14, 2005.
Revised February 22, 2005.
Accepted for publication February 23, 2005.

Characterization of the T-cell response in a patient with phenindione hypersensitivity

Abstract

The oral anticoagulant phenindione is associated with hypersensitivity reactions in 1.5-3% of patients, the pathogenesis of which is unclear. We describe a patient who developed a severe hypersensitivity reaction that involved both the skin and lungs. A lymphocyte transformation test showed proliferation of T cells from the hypersensitive patient, but not from 4 controls, on exposure to phenindione in vitro. Drug-specific T-cell clones were generated and characterised in terms of their phenotype, functionality, and mechanism of antigen presentation. Forty three-HLA class II restricted CD4+ T-cell clones were identified. T-cell activation resulted in the secretion of IFN- and IL-5. Five out of seven clones proliferated with phenindione alone, while two clones also proliferated with 2-phenylindene. Certain T-cell clones were also stimulated by R- and S-warfarin; computer modelling revealed that warfarin can adopt a phenindione-like structure. Phenindione was presented to T-cells via two pathways: first, bound directly to MHC; and secondly, bound to a processed peptide. Our data show that CD4+ T-cells are involved in the pathophysiology of phenindione hypersensitivity. There may be cross-sensitivity with warfarin in some phenindione hypersensitive patients.

Key words: antigen presentation, antigen processing, drug hypersensitivity, phenindione, t-lymphocytes, warfarin