Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine.
To investigate how T cells are involved in hypersensitivity reactions to drugs that become immunogenic after metabolization, e.g., sulfonamides and antiepileptics, we analyzed in vitro the drug-induced activation of CD4+ and CD8+ T cell subsets, cytokine secretion, TCR V beta distribution, and proliferation of T cells from four drug-allergic individuals. In addition, the activation parameters CD25 and HLA-DR were analyzed in vivo on CD4+ and CD8+ T cells from five patients with acute drug allergies, some of them with anticonvulsant hypersensitivity syndrome with hepatitis. Our results show that, in vitro, drug-induced proliferation of PBMC from patients with allergy to sulfamethoxazole, phenytoin, or carbamazepine was specific and dose dependent. CD4+ as well as CD8+ T cells expressed elevated levels of CD25 and HLA-DR molecules after drug stimulation. Drug-activated lymphocytes secreted high amounts of IL-5 and normal or low levels of IL-2, IFN-gamma, IL-4, and TNF-alpha. An enhanced expansion of TCR V beta 17+ T cells 9 days after in vitro stimulation with sulfamethoxazole was observed in one patient with sulfamethoxazole allergy. The drug specificity of the in vitro-activated T cells was confirmed by generation of different sulfamethoxazole specific T cell lines and CD4+ and CD8+ T cell clones. T cell analysis of patients with acute drug allergy to carbamazepine, phenytoin, allopurinol, or paracetamol confirms the in vitro data, because all patients had activated CD4+ or CD8+ T cells in the circulation. Our data clearly show the involvement of drug-specific T cells in drug allergies.
Mauri-Hellweg
D
D
Institute of Immunology and Allergology, Inselspital, Bern, Switzerland.
Bettens
F
F
Mauri
D
D
Brander
C
C
Hunziker
T
T
Pichler
W J
WJ
D000927:Anticonvulsants / Q000009:adverse effects*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002220:Carbamazepine / Q000009:adverse effects; D002460:Cell Line; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000209:etiology*; D006684:HLA-DR Antigens / Q000502:physiology; D006801:Humans; D015848:Interleukin-5 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000378:metabolism; D010672:Phenytoin / Q000009:adverse effects; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000502:physiology; D013449:Sulfonamides / Q000009:adverse effects*
D000927:Anticonvulsants; D016207:Cytokines; D006684:HLA-DR Antigens; D015848:Interleukin-5; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D013449:Sulfonamides; D002220:Carbamazepine; D010672:Phenytoin