Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes

Purpose: To further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8(+) T lymphocytes in humans. Methods: In 15 healthy subjects (9 female (60%), 35.7 +/- 12.1 years), apoptosis and cytotoxic function of CD8(+) T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10 mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2 h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8(+) T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR). Results: High concentration of LEV decreased perforin release of CD8(+) T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5-35.9%) vs. 16.6% (IQR 12-24.9%), p = 0.002). LEV had no influence on apoptosis and proliferation (p > 0.05). VPA (100 mg/L) slowed apoptosis of CD8(+) T lymphocytes after 24 h (VPA 100 mg/L vs. control: 7.3% (IQR 5.4-9.5%) vs. 11.3% (IQR 8.2-15.1%), p < 0.001), but had no effects on perforin release (p > 0.05). SV2A protein was detected in CD8(+) T lymphocytes. Conclusion: LEV decreased degranulation of CD8(+) T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect. (C) 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.