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Development of a new immunosuppressive strategy by targeting pyrimidine synthesis

通过靶向嘧啶合成开发新的免疫抑制策略

基本信息

批准号：
15390388
负责人：
SHIMAMURA Tsuyoshi
金额：
$ 7.55万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Leflunomide is a strong immunosuppressant that exerts its effect by blocking de novo pyrimidine synthesis. It has been shown that Leflunomide is a useful immunosuppressive agent in clinical trials of autoimmune diseases. However, due to the drug's long half-life, Leflunomide has never been clinically applied in the field of organ transplantation. A new Leflunomide derivative, FK778 and FK779, that has a shorter half-life than its mother drug were developed to resolve such problem. In this study, we have examined immunosuppressive effect, pharmacokinetics and side-effects of FK778 and FK779 in rat heart transplantation and dog kidney transplantation. In addition, we assessed immunosuppressive effect of FK778 and FK779 in combination with calcineurin inhibitors, tacrolimus (TAC) and cydosporine (CsA). In both rat and dog transplantation models, FK778 and/or FK779 prolonged allograft survival Also, there was an additive or synergistic effect when given with these calcineurin inhibitors. In a dog transplantation model, a slight leukocytopenia and anemia was observed when FK778 was administered at 6 mg/kg/day ; however, no serious side-effect was noted. We further examined an immunosuppressive effect of FK779 in a hamster-to-rat heart xenotransplantation model. FK779 effectively controlled both acute vascular and acute cellular xenograft rejections and markedly prolonged xenograft survival when combined with calcineurin inhibitors (TAC/CsA) or CD40-CD154/B7-CD28 costimulation blockades. We conclude that FK778 and FK779 are powerful and useful immunosuppressant that has a potential for clinical application in organ transplantation.

来氟米特是一种强免疫抑制剂，通过阻断嘧啶从头合成发挥其作用。来氟米特是一种有效的免疫抑制剂，在自身免疫性疾病的临床试验中已被证明。但由于药物半衰期长，来氟米特从未在器官移植领域进行过临床应用。为了解决这一问题，开发了一种新的来氟米特衍生物FK 778和FK 779，其半衰期比其母体药物短。本研究观察了FK 778和FK 779在大鼠心脏移植和犬肾移植中的免疫抑制作用、药代动力学和不良反应。此外，我们评估了FK 778和FK 779与钙调磷酸酶抑制剂他克莫司（TAC）和环孢菌素（CsA）联合使用的免疫抑制作用。在大鼠和犬移植模型中，FK 778和/或FK 779延长了同种异体移植物的存活率。此外，与这些钙调磷酸酶抑制剂联合给药时，存在累加或协同效应。在犬移植模型中，以6 mg/kg/天剂量给予FK 778时，观察到轻微白细胞减少和贫血;但未观察到严重副作用。我们进一步检查了FK 779在仓鼠-大鼠异种心脏移植模型中的免疫抑制作用。当与钙调磷酸酶抑制剂（TAC/CsA）或CD 40-CD 154/B7-CD 28共刺激阻断剂联合使用时，FK 779可有效控制异种移植物的急性血管和急性细胞排斥反应，并显著延长异种移植物的生存期。FK 778和FK 779是一种有效的免疫抑制剂，在器官移植中具有潜在的临床应用价值。