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TOXICOLOGY

Characterization of the T-Cell Response in a Patient with Phenindione Hypersensitivity

Departments of Pharmacology (D.J.N., J.F., P.J.C., J.E.H., M.P., B.K.P.) and Chemistry (N.G.B.), The University of Liverpool, Liverpool, England

The oral anticoagulant phenindione [2-phenyl-1H-indene-1,3(2H)-dione] is associated with hypersensitivity reactions in 1.5 to 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 four controls on exposure to phenindione in vitro. Drug-specific T-cell clones were generated and characterized in terms of their phenotype, functionality, and mechanism of antigen presentation. Forty-three human leukocyte antigen class II restricted CD4⁺ T-cell clones were identified. T-cell activation resulted in the secretion of interferon- and interleukin-5. Five of seven clones proliferated with phenindione alone, whereas two clones also proliferated with 2-phenylindene. Certain T-cell clones were also stimulated by R- and S-warfarin; computer modeling revealed that warfarin can adopt a phenindione-like structure. Phenindione was presented to T-cells via two pathways: first, bound directly to major histocompatibility complex and second, 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.

Address correspondence to: Dr. Dean J. Naisbitt, Department of Pharmacology and Therapeutics, Sherrington Building, Ashton Street, The University of Liverpool, P.O. Box 147, Liverpool, L69 3GE, England. E-mail:dnes{at}liv.ac.uk