Immunosuppressive mode of action of deoxyspergualin and deoxymethylspergualin

1)体外模型（人）与环孢素（CYA）和FK506比较，评价脱氧甲基spergualin （MeDSG）对体外人淋巴细胞反应的影响。采用正常人外周血单核细胞（PBMN）进行混合淋巴细胞反应（MLR）试验。通过PHA、IL2和OKT3介导的细胞介导的13、mpholys （CML）和囊胚发生。MEDSG仅抑制同种异体刺激（MI、R和CML）和il - 2诱导的囊胚发生，而不抑制PHA或OKT3诱导的囊胚发生，尽管其他免疫抑制剂在所有实验中都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天添加MEDSG， MLR的抑制活性也没有降低。而在MLR后期加入FK506和CYA，抑制活性下降。在变态刺激中，MeDSG也作用于细胞毒性效应细胞生成的相对早期阶段。2)体内模型（大鼠）本研究研究了短时间DSG治疗大鼠同种异体心脏移植后的存活情况，以及DSG诱导同种异体心脏移植早期存活的机制。雄性LEW大鼠作为受体，雄性ACI大鼠和Wister大鼠分别作为供体和第三方供体。短疗程的DSG治疗，从移植第4天开始，显著延长了LEW受者ACI心脏移植的生存期，2.5mg/kg/天和5天的平均生存期分别为16.6+5.8天和29.8+3.0天。Omg /公斤/天,分别。移植后第20天。通过多种检测系统检测脾脏细胞或血清的能力，进一步分析dsg诱导同种移植物存活的机制。与对照组相比，经dsg处理的同种异体心脏移植存活大鼠脾细胞对供体刺激细胞无增殖反应。同种异体心脏移植存活大鼠脾细胞对供体靶细胞的毒活性低于同种异体心脏移植排斥大鼠脾细胞。在供株和第三方MLR中，将不同浓度的DSG处理过的存活ACI心脏同种异体移植LEW大鼠的脾脏细胞或血清添加到MLR中，均显示出细胞剂量依赖性和血清剂量依赖性的强烈抑制作用。无论是ACI心脏移植还是第三方Wister心脏移植，将来自DSG处理的LEW大鼠的2.0x10^8个脾脏细胞或2ml senn转移到亚致死照射的移植宿主中，都不能延长存活时间。这些结果表明，DSG在全移植物存活大鼠的早期处理可降低增殖反应和细胞毒性活性，诱导抑制细胞和体液因子。少

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