Author/Authors :
Koo، نويسنده , , Gloria C. and Blake، نويسنده , , Joseph T. and Shah، نويسنده , , Kashmira and Staruch، نويسنده , , Mary Jo and Dumont، نويسنده , , Francis and Wunderler، نويسنده , , Denise and Sanchez، نويسنده , , Manuel and McManus، نويسنده , , Owen B. and Sirotina-Meisher، نويسنده , , Anna and Fischer، نويسنده , , Paul and Boltz، نويسنده , , Robert C. and Goetz، نويسنده , , Michael A. and Baker، نويسنده , , Robert and Bao، نويسنده , , Jianming and Kayser، نويسنده , , Frank and Rupprecht، نويسنده , , Kathleen M. and Parsons، نويسنده , , William H. and Tong، نويسنده , , Xin-Chun and Ita، نويسنده , , Ida E. and Pivnichny، نويسنده , , Jim and Vincent، نويسنده , , Stella and Cunningham، نويسنده , , Paul and Hora Jr.، نويسنده , , Don and Feeney، نويسنده , , William and Kaczorowski، نويسنده , , Gregory S Springer، نويسنده , , Martin S.، نويسنده ,
Abstract :
The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.
