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

Abstract

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.

• Authors: Dean J Naisbitt, John Farrell, Peter J Chamberlain, Josephine E Hopkins, Neil G Berry, Munir Pirmohamed, B Kevin Park
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 313 Issue 3 Pg. 1058-65 (Jun 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15743920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-5
• Phenindione
• Interferon-gamma

Topics

• Drug Hypersensitivity (immunology)
• Female
• Humans
• Interferon-gamma (biosynthesis)
• Interleukin-5 (biosynthesis)
• Lymphocyte Activation
• Middle Aged
• Models, Molecular
• Phenindione (adverse effects)
• T-Lymphocytes (immunology)