Grant-in-Aid for Scientific Research (A).
|Research Institution||HOKKAIDO UNIVERSITY|
TODO Satoru Hokkaido Univ., Grad.School of Med., Pro., 大学院・医学研究科, 教授 (60136463)
大村 孝志 北海道大学, 医学部・附属病院, 助手 (40312350)
FURUKAWA Hiroyuki Univ., Medical Hosp.., Lec., 医学部・附属病院, 講師 (70292026)
陳 孟鳳 北海道大学, 医学部・附属病院, 医員
MATSUSHITA Michiaki Hokkaido Univ., Grad.School of Med., Asso.Pro., 大学院・医学研究科, 助教授 (20250425)
嶋村 剛 北海道大学, 医学部・附属病院, 医員
JIN Meang bong Hokkaido Univ., Medical Hosp., Physician
SHIMAMURA Tsuyoshi Hokkaido Univ., Medical hosp., Physician
|Project Fiscal Year
1998 – 2000
Completed(Fiscal Year 2000)
|Budget Amount *help
¥33,000,000 (Direct Cost : ¥33,000,000)
Fiscal Year 2000 : ¥7,800,000 (Direct Cost : ¥7,800,000)
Fiscal Year 1999 : ¥22,600,000 (Direct Cost : ¥22,600,000)
Fiscal Year 1998 : ¥2,600,000 (Direct Cost : ¥2,600,000)
|Keywords||1Cyclosporine / tacrolimus / FTY720 / KF20444 / FK778 / FK779 / SZD-RAD / A802715 / CTLA4Ig / サイクロスポリン / タクロリムス / 臓器移植 / ラット / イヌ / 心臓 / 腎臓 / 免疫抑制剤 / 肝移植 / 心移植 / 腎移植 / 免疫寛容|
To develop innovative strategies for transplant immunosuppression, we tested 7 brand new drugs, FTY720, KF20444, FK778, FK779, SZD-RAD, A802715, and CTLA4Ig for a-single-dose study or for a combined dose study with conventional immunosuppressants(cyclosproine(CsA)or tacrolimus(FK506)).
FTY720 prolonged both cardiac and liver allograft survival in ACI to LEW rat organ transplantation. FTY720 has a wide therapeutic window without an adverse effect and synergistic effect with CsA and FK506 in rat allografts. FTY also exhibited immunosuppressive effects on canine renal and hepatic allografts. The immunosuppressive potency was not as strong as CsA or FK506 in canine allografts transplantation, although the therapeutic range was also wide.
KF20444 showed significant immunosuppressive effect in ACI to LEW rat cardiac transplantation, although severe gastrointestinal toxicity was observed over the dose of 4mg/kg/day. Intermittent administration was done in attempt to reduce toxicity with prolong
ed graft survival compared to the most optimal one by daily administration.
FK778/FK779 showed a significant prolonged survival in ACI to LEW rat cardiac transplantation. The combination therapy with FK778/FK779 and CsA, or FK506 also prolonged allografts survival. In canine renal transplantation, FK778 monotherapy(4mg/kg/day and 6mg/kg/day)and combination therapy with FK506(0.5mg/kg/day)also prolonged allografts survival.
SDZ-RAD showed significant prolonged allografts survival in ACI to LEW rat liver transplantation. The combination therapy SDZ-RAD and CsA also showed marked immunosuppressive effect in the same model.
A802715 monotherapy did not show immunosuppressive effect in ACI to LEW rat cardiac and liver transplantation, while the combination therapy with A802715 and CsA exhibited a synergic effect on prolongation of allografts survival in WKAH to PVG rat cardiac transplantation.
CTLA4Ig worked as an immunosuppressive agent on rat orthotopic small intestine transplantation when it was administrated into abdominal cavity during 7 successive days after surgery. Less