Abstract
Background
Delayed hypersensitivity is responsible for severe cutaneous adverse drug reactions
(cADRs), especially in Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis,
and drug-induced hypersensitivity syndrome (DIHS) (also known as drug rash with eosinophilia
and systemic symptoms [DRESS] syndrome). The drug-induced lymphocyte stimulation test
(DLST), or lymphocyte transformation test (LTT), is used to identify the culprit drug
in severe cADR cases.
Objective
The aim of this study was to examine the immune reactions in cADR patients through
the identification of the drug-specific proliferating cells by flow cytometric DLST
(FCM-DLST).
Methods
The peripheral blood mononuclear cells of 16 anticonvulsant-induced cADR patients
were investigated by conventional DLST and a FCM-DLST protocol in which CFSE dilution
and BrdU incorporation were combined. FCM-DLST allowed for the identification of the
drug-specific proliferating cells in six cases. Three of these cases were DIHS cases,
whereas there was one case of SJS, one case of maculopapular rash (MP), and one case
of erythema multiforme (EM) among the six cases.
Results
In FCM-DLST, drug-specific proliferating T cells were detected as CFSElow BrdUhigh cells. These cells corresponded to the cells incorporating 3H-thymidine in conventional DLST. Although CD4+ T-cell proliferation dominated the observed proliferation in most of the cases (in
the recovery stage of the three DIHS cases, the MP case, and the EM case), drug-specific
CD8+ cytotoxic T lymphocytes (CTLs) were detected, especially in the acute stages of the
SJS case and one of the DIHS cases. There was a dramatic switch in the predominant
drug-specific proliferating T-cell population in the course of one of the cases of
DIHS in which CD8+ CTLs were predominant initially, whereas CD4+ T cells were predominant later. Moreover, drug-specific CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) proliferated during the recovery stage in one DIHS case.
Conclusions
FCM-DLST revealed that the cell proliferation detected by conventional DLST is a heterogeneous
proliferation of both CD8+ CTLs and CD4+ T cells that likely includes Tregs. However, the number of cADR cases in this study
was limited, which limits the conclusions that can be drawn from it.
Keywords
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Article info
Publication history
Published online: January 09, 2012
Accepted:
December 2,
2011
Received in revised form:
November 22,
2011
Received:
August 24,
2011
Identification
Copyright
© 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Inc. All rights reserved.
