Immunosuppressive mode of action of deoxyspergualin and deoxymethylspergualin

1)在体外模型(人)中，以环孢素(CyA)和FK506为对照，观察了脱氧甲基精胺(MeDSG)对体外人淋巴反应的影响。用正常人外周血单个核细胞(PBMN)检测混合淋巴细胞反应(MLR)。细胞介导的13，mpholys is(CML)和PHA，IL2，OKT3诱导的BALB细胞生成。MEDSG仅抑制同种异体刺激(MI。R和CML)和IL2诱导原始细胞生成，而不是PHA或OKT3诱导原始细胞生成，尽管其他免疫抑制剂对所有检测结果都有一定的抑制作用。MLR动力学研究表明，即使在MLR的第3天或第4天加入MEDSG，抑制活性也不会降低。而FK506和CyA在MLR后期加入时，抑制活性有所下降。在同种异体刺激中，MeDSG也作用于细胞毒效应细胞产生的相对早期阶段。2)在活体小鼠中，在本研究中，心脏…存活在早期阶段，研究了短疗程的DSG治疗后大鼠移植心脏的增加以及DSG诱导的同种异体心脏移植存活的机制。受体为雄性LEW大鼠，供体为雄性ACI和Wister大鼠，供体为第三方供体。从移植后第4天开始，短程DSG可显著延长移植ACI移植物的存活时间，2.5 mg/kg/d和5.0 mg/kg/d的平均存活时间分别为16.6±5.8天和29.8±3.0天。通过检测脾细胞或血清在几种检测系统中的能力，进一步分析了DSG治疗后诱导移植物存活的机制。与对照组相比，DSG处理的同种异体心脏移植存活大鼠的脾细胞对供体刺激细胞没有增殖反应。DSG处理的同种异体心脏移植存活大鼠的脾细胞对供体品系靶细胞的杀伤活性低于排斥同种异体心脏移植大鼠。在供者品系和第三方MLR中，加入不同浓度的DSG处理的LEW大鼠存活的ACI同种异体心脏移植后的脾细胞或血清对MLR均显示出强烈的抑制作用，且呈细胞剂量依赖性和血清剂量依赖性。无论是在ACI心脏移植物中，还是在第三方Wister心脏移植物中，将DSG处理的LEW大鼠的2.0×10~(-8)脾细胞或2mlSenn移植到亚致死量照射的移植物上均不能延长存活时间。这些结果表明，在移植肾存活的早期，DSG可降低大鼠的增殖反应和细胞毒活性，并诱导抑制细胞和体液因子。较少

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