Immunosuppressive mode of action of deoxyspergualin and deoxymethylspergualin

脱氧精胍菌素和脱氧甲基精胍菌素的免疫抑制作用方式

• 批准号: 01570892
• 负责人: TAKAHARA Shiro
• 金额: $ 1.34万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570892/
• 关键词: Mixed Lymphocyte Reaction; Cell Mediated Lympholysis; Deoxyspergualin; Deoxymethylspergualin; Immunosuppressive Agent; Organ Transplantation; メチルデオキシスパガリン

1)ln vitro modet(human)The effect of Deoxymethylspergualin (MeDSG) on 'in vitro' human lymphoc e response was assessed in comparison with ciclosporin (CYA) and FK506. Peripheral blood mononuclear (PBMN) cells from normal human volunteers were used for assays of mixed lymphocyte reaction (MLR). cell mediated 13, mpholys is (CML) and blastogenesis by PHA, IL2 and OKT3. MEDSG suppressed only allogeneic stimulation (MI. R and CML) and IL2 induced blastogenesis but not PHA or OKT3 induced blastogenesis, although the other immunosuppressive agents showed some suppressive effects for all assays. Kinetic study of MLR showed that the suppressive activity did not decrease even when MEDSG was added at day 3 or day 4. FK506 and CYA, however, showed a decline of suppressive activity when added at a later phase of MLR. MeDSG also acted on the comparatively early phase of cytotoxic effecter cell generation in allogerieic stimulation.2)ln vivo mociel (rat)In the present study, the survival of heart al … More lograft in rats after a short course of DSG treatment and the mechanism underlying DSG-induced heart allograft survival, in the early phase, were studied. Male LEW rats were used as recipients& Male ACI and Wister rats were used as donors and and the third party donors, respectively. Survival of ACI lieart grafts in LEW recipients treated with a short course of DSG, beginning from day 4 of grafting, were markedly prolonged, with a mean survival time of 16.6+5.8 days and 29.8+3.0 days at the dose of 2.5mg/kg/day and 5. Omg/kg/day, respectively.On day 20 postgrafting. the mechanism of inducing alograft survival after DSG-treatment was further analyzed by testing the ability of spleen cells or serum in several assay systems. Spleen cells from DSG-treated rat with surviving heart allograft showed no proliferative response against donor strain stimulator cells compared with the control. The cytotoxic activity of spleen cells from DSG-treated rat with surviving heart allograft was lower than the spleen cells from rat with rejected heart allograft towards donor strain target cells. Adding various concentrations o-f spleen cells or serum from DSG treated LEW rat with surviving ACI heart allograft to MLR revealed a strong suppression, in a cell-dose-dependent manner and serum-dose-dependent manner, both in donor strain and third party MLR.Moreover. transfer of 2.0x10^8 spleen cells or 2 ml senn from DSG treated LEW rat with siuwiving ACI heart allograft to sublethal irradiated grafted host did not prolong survival, both in ACI heart grafts and third party Wister heart grafits. These results suggest that proliferative response and cytitoxic activity are decreased and suppressor cells and humoral factorps')are induced, by treatment with DSG in the early phase of rats with surviving allgraft. Less

1）体外模型（人）：以环孢素（CYA）和FK 506为对照，观察了脱氧甲基精胍菌素（MeDSG）对体外人淋巴细胞反应的影响。采用正常人外周血单个核细胞（PBMN）进行混合淋巴细胞反应（MLR）试验。细胞介导的13，mpholys（CML）和PHA，IL 2和OKT 3的胚细胞发生。MEDSG仅抑制同种异体刺激（MI. R和CML）和IL 2诱导胚细胞发生，但PHA或OKT 3不诱导胚细胞发生，尽管其他免疫抑制剂对所有测定均显示出一定的抑制作用。MLR的动力学研究表明，即使在第3天或第4天加入MEDSG，抑制活性也没有降低。FK 506和CYA在MLR后期加入时抑制活性下降。MeDSG还作用于同种异体刺激中细胞毒性效应细胞产生的相对早期阶段。2）在体小鼠（大鼠） ...更多信息 本实验研究了DSG短期处理后大鼠移植心脏的存活情况，并探讨了DSG诱导大鼠移植心脏存活的早期机制。雄性LEW大鼠用作受体，雄性ACI和Wister大鼠分别用作供体和第三方供体。从移植第4天开始接受短期DSG治疗的LEW受者的ACI心脏移植物的存活时间明显延长，在2.5mg/kg/d和5.0mg/kg/d剂量下的平均存活时间分别为16.6 ± 5.8天和29.8 ± 3.0天。移植后第20天，通过在几种测定系统中测试脾细胞或血清的能力，进一步分析DSG处理后诱导同种移植物存活的机制。与对照组相比，经DSG处理的心脏移植物存活大鼠的脾细胞对供体菌株刺激细胞没有表现出增殖反应。DSG处理的心脏移植存活大鼠脾细胞对供体系靶细胞的杀伤活性低于心脏移植排斥大鼠脾细胞。加入不同浓度的DSG处理的存活ACI心脏移植LEW大鼠的脾细胞或血清对供体和第三方MLR的MLR均表现出强烈的抑制作用，并呈细胞剂量依赖性和血清剂量依赖性。将2.0 × 10^8个脾细胞或2 ml来自DSG处理的LEW大鼠的senn移植到亚致死剂量的照射移植宿主中，无论是ACI心脏移植物还是第三方Wister心脏移植物，都不能延长存活时间。这些结果表明，在移植物存活大鼠的早期阶段，用DSG处理可降低增殖反应和细胞毒活性，诱导抑制细胞和体液因子。少

项目成果

S. Takahara, Y. Takano, H. Kameoka, Y. kokado, M. Ishibashi, A. Okuyama and T. Sonoda: "The experience of administration of 15-deoxyspergualin on rejection in kidney transplant recipients." Transplant Proc.

S. Takahara、Y. Takano、H. Kameoka、Y. kokado、M. Ishibashi、A. Okuyama 和 T. Sonoda：“15-脱氧精胍菌素治疗肾移植受者排斥反应的经验。”

Y. Takano, , S. Yakahara, . Jiang, A. Moutabarrik, M. Ishibashi, H. Kameoka, HY. Kokado and T. Sonoda: "Kinetic study of immunosuppressive effects of deoxymethylspergualin." J American Society of Nephrology. 1. 753 (1990)

Y. Takano，，S. Yakahara，。

S.Takahara,Y.Takano,et al: "The experience of administration of 15ーdeoxyspergualin on rejection in kidney transplant recipients." Transplant Proc.

S. Takahara、Y. Takano 等人：“15-脱氧精胍菌素治疗肾移植受者排斥反应的经验”。

S.Takahara,Y.Takano,et al: "The experinece of administration of 15-deoxyspergualin on rejection in kidney transplant recipients." Transplant Proc.

S.Takahara、Y.Takano 等：“15-脱氧精胍菌素治疗肾移植受者排斥反应的经验”。

H. Jiang, S. Takahara, Y. Kokado, M. Ishibashi and T. Sonoda: "In vitro immunosuppressive effect : A comparative study between deoxymethylspergualin and cyclosporin A, on human lymphocyte responses." J Clin Lab Immunol. 33. 75-81 (1990)

H. Jiang、S. Takahara、Y. Kokado、M. Ishibashi 和 T. Sonoda：“体外免疫抑制作用：脱氧甲基精胍菌素和环孢菌素 A 对人类淋巴细胞反应的比较研究”。