Thèse de doctorat en Biologie - Immunologie
Sous la direction de Philippe Musette.
Soutenue en 2014
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug-induced reaction that involves both the skin and the viscera. Several herpesvirus family members including EBV or HHV-6 can be found reactivated coincidently with various clinical symptoms in DRESS. In addition, we have previously identified activated EBV specific cytotoxic CD8+ T cells as major actors in the pathophysiology of DRESS. Furthermore, gene expression profiling from DRESS patients revealed that IL-10 and TNFα were two of the most upregulated mRNA in PBMCs and in CD8+ T lymphocytes respectively. Interestingly, IL-10 plays a key role in the immunomodulation and EBV replication while TNFα is highly implicated in the inflammation process during DRESS. However, direct drug effect on cytokines secretion and its relationship with viral reactivation has not been studied. We thus measured IL-10 and TNFα secretion levels in DRESS patients’ serum, in control patients taking DRESS inducer drugs without adverse effect and B-LCL lines following incubation with DRESS inducer drugs for 72 hours. We analyzed the presence of IL-10 and TNFα by ELISA and FACS. We show that DRESS patients as well as patients taking drugs without adverse effect have an increase of IL-10 and TNFα in their serum at the onset of the disease. In vitro, we demonstrate that some DRESS inducer drugs namely SMX and VPA reduce significantly the IL-10 secretion in B-LCL from DRESS patients but not from healthy donors by sequestering IL-10 in the cytoplasm. Interestingly, the same observation was obtained for TNFα in DRESS patients and healthy donors B-LCL, with however differential effect depending of the drugs regarding the sequestering of TNFα also in the cytoplasm of B cells. The balance between IL-10 and TNFα is affected by DRESS inducer drugs specifically in DRESS patients and viral reactivation seems to play a key role in cytkine release. These findings allow a better understanding of the physiopathology of the DRESS syndrome and drug induced hypersensitivity.
Modulation of IL-10 and TNFα secretion in drug reactions with eosinophilia and systemic symptoms (DRESS)
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