Nathens A B, Rotstein O D, Jones J J, Dackiw A P, Gorczynski R
The Toronto Hospital, University of Toronto, Toronto, M5G 2C4, Canada.
J Surg Res. 1998 Jun;77(1):75-9. doi: 10.1006/jsre.1998.5338.
Intercellular adhesion molecule 1 (ICAM-1) plays an important role in mediating allograft rejection through its role in cellular trafficking and as an important costimulatory signal mediating T cell activation. We have previously reported that systemic administration of the glutathione (GSH) depleting agent diethylmaleate (DEM) prevents upregulation of ICAM-1 in various inflammatory models, suggesting that this agent may offer benefit in preventing allograft rejection. Thus we evaluated the effects of DEM in a murine model of renal transplantation.
Kidneys from C57BL/6 mice were transplanted into MHC incompatible C3H mice. Donors were treated with DEM 1 h prior to sacrifice, whereas recipients received DEM 1 h following transplantation. Animals were followed until the time of death. In separate studies, renal ICAM-1 mRNA expression was evaluated by polymerase chain reaction and the CD4(+) T cell cytokine profile evaluated in a mixed lymphocyte reaction using C3H responder splenocytes and C57BL/6 stimulator cells.
Pretreatment with DEM increased survival from 18.9 +/- 3.6 to 30.6 +/- 10 days (P < 0.05). This increase in survival was associated with a reduction in renal ICAM-1 mRNA expression. Mixed lymphocyte cultures derived from animals pretreated with DEM demonstrated a reduction in the Th1 cytokines IFN-gamma and IL-2 and an increase in the Th2 cytokines IL-4 and IL-10.
Administration of DEM with consequent systemic GSH depletion significantly reduces allograft ICAM-1 expression and prolongs graft survival. Although speculative, a shift from a Th1 to a Th2 cytokine response raises the possibility that tolerance induction plays a role in prolonged allograft survival.
细胞间黏附分子1（ICAM-1）在介导同种异体移植排斥反应中发挥重要作用，它参与细胞转运，并作为介导T细胞活化的重要共刺激信号。我们之前报道过，系统性给予谷胱甘肽（GSH）消耗剂马来酸二乙酯（DEM）可防止ICAM-1在各种炎症模型中上调，提示该药物可能对预防同种异体移植排斥反应有益。因此，我们在小鼠肾移植模型中评估了DEM的作用。
将C57BL/6小鼠的肾脏移植到MHC不相容的C3H小鼠体内。供体在处死前1小时接受DEM处理，而受体在移植后1小时接受DEM处理。观察动物直至死亡。在单独的研究中，通过聚合酶链反应评估肾脏ICAM-1 mRNA表达，并使用C3H反应性脾细胞和C57BL/6刺激细胞在混合淋巴细胞反应中评估CD4(+) T细胞细胞因子谱。
DEM预处理使生存期从18.9±3.6天延长至30.6±10天（P<0.05）。生存期的延长与肾脏ICAM-1 mRNA表达的降低有关。来自用DEM预处理的动物的混合淋巴细胞培养物显示Th1细胞因子IFN-γ和IL-2减少，而Th2细胞因子IL-4和IL-10增加。
给予DEM导致全身性GSH消耗可显著降低同种异体移植ICAM-1表达并延长移植物存活时间。虽然只是推测，但从Th1细胞因子反应向Th2细胞因子反应的转变增加了耐受性诱导在延长同种异体移植存活时间中起作用的可能性。
