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 CD4ϩ ␣␤ 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 ϩ T-cells are involved in the pathophysiology of phenindione hypersensitivity. There may be cross-sensitivity with warfarin in some phenindione hypersensitive patients.

Idiosyncratic Adverse Drug Reactions: Current Concepts

“…First, drugs that do not themselves bind covalently to nucleophilic amino acids stimulate T cells via their T-cell receptor in an MHC restricted manner; second, fixation of antigen presenting cells, which blocks protein processing, does not prevent the drugspecific activation of certain clones; third, the kinetics of drug-specific T-cell receptor triggering and calcium signaling are too quick to allow protein processing; and finally, the removal of soluble drug through repeated washing of drug-treated antigen presenting cells prevents MHC-restricted drug presentation and T-cell activation. These findings have been replicated by several independent research groups using an increasing number of drugs Schnyder et al, 1997;Hashizume et al, 2002;Naisbitt et al, 2003bNaisbitt et al, , 2005Nassif et al, 2004;Wu et al, 2006;Keller et al, 2010 ).…”

The Generation, Detection, and Effects of Reactive Drug Metabolites

“…The main justifications for this theory are as follows: The time taken for activation of T‐cell clones is much too rapid for metabolism and antigen processing to be a determining factor Both T‐cell clones and peripheral blood mononuclear cells (PBMCs) cultured from the same patient respond to the parent drug without metabolism taking place The presence of drug/chemical is required for the activation: if the drug is washed away, the T‐cell response is diminished/abolished …”

In vitro Tests of T-Cell-Mediated Drug Hypersensitivity

“…Positive patch test reactions after 24-48 h, positive in vitro reactivity in lymphocyte transformation tests (LTT; 3 H-thymidine incorporation), and in particular the generation of drugspecific T-cell lines and T-cell clones (TCCs) from the blood of patients with different forms of drug hypersensitivities such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) clearly demonstrate that drugspecific T cells can be detected in the affected tissue and peripheral blood of drug-allergic patients [4][5][6][7][8][9][10] . In addition, a newer study clearly showed that 1: 250 to 1: 10,000 of T cells in the peripheral blood of drug-allergic patients are reactive to the relevant drug.…”