Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes

Abstract

PurposeTo 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. MethodsIn 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 (5mg/L and 50mg/L) and VPA (10mg/L and 100mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1h or 24h. Cytotoxic function was assessed following 2h 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). ResultsHigh concentration of LEV decreased perforin release of CD8+ T lymphocytes (LEV 50mg/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 (100mg/L) slowed apoptosis of CD8+ T lymphocytes after 24h (VPA 100mg/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. ConclusionLEV 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.