Characterization of the T-cell response in a patient with phenindione hypersensitivity.
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(+) alphabeta T-cell clones were identified. T-cell activation resulted in the secretion of interferon-gamma 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.
Naisbitt
Dean J
DJ
Department of Pharmacology, The University of Liverpool, England. dnes@liv.ac.uk
Farrell
John
J
Chamberlain
Peter J
PJ
Hopkins
Josephine E
JE
Berry
Neil G
NG
Pirmohamed
Munir
M
Park
B Kevin
BK
D004342:Drug Hypersensitivity / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008875:Middle Aged; D008958:Models, Molecular; D010630:Phenindione / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000276:immunology*
D015848:Interleukin-5; D010630:Phenindione; D007371:Interferon-gamma