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短期使用布雷喹那钠治疗预防大鼠原位肝移植排斥反应。移植肝内细胞因子基因表达分析。

Prevention of orthotopic liver allograft rejection in rats with a short-term brequinar sodium therapy. Analysis of intragraft cytokine gene expression.

作者信息

Shirwan H, Cosenza C A, Wang H K, Wu G D, Makowka L, Cramer D V

机构信息

Transplantation Biology Research Laboratory, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048.

出版信息

Transplantation. 1994 Apr 15;57(7):1072-80.

PMID:8165706
Abstract

Brequinar sodium (BQR) is a new immunosuppressive drug that is highly effective in preventing graft rejection in several different experimental settings, including primary allografts and xenografts. A short course of BQR treatment during the onset of allograft rejection can induce the permanent survival of liver and kidney allografts in rats. To study the molecular basis of BQR-induced prolongation of allograft survival, we analyzed the intragraft pattern of IL-1 alpha, IL-2, IL-2R, IL-4, IL-6, IL-10, and TNF gene expression in the ACI-to-LEW liver allograft model. A semiquantitative polymerase chain reaction was developed to measure cytokine gene expression in control and BQR-treated liver graft recipients at various days after transplantation. Untreated control liver allografts expressed all of the cytokines analyzed. There was a marked increase in the steady state level of transcripts for each cytokine as graft rejection proceeded. The treatment of liver graft recipients with 12 mg/kg/day of BQR on days 6, 7, and 8 after transplantation suppressed the expression of all these cytokines within 24 hr of administration. The early suppression of cytokine expression was associated with a modest but distinct reduction in the infiltration of inflammatory cells into the liver grafts. The reduction in the level of transcripts for IL-4, IL-6, and IL-10 persisted in long-term survivors (30 days after transplantation). In contrast, there was a significant increase in the level of transcripts for IL-1 alpha, IL-2, and IL-2R in these long-term survivors. Our results demonstrated clearly that the pattern of cytokine gene expression during allograft rejection is significantly altered by a 3-day course of therapy with BQR. The temporary down-regulation of cytokine gene expression may be responsible for an altered immunological state that results in the prolonged survival of liver allografts.

摘要

布雷喹那钠(BQR)是一种新型免疫抑制药物,在多种不同的实验环境中,包括在原发性同种异体移植和异种移植中,对预防移植物排斥反应都非常有效。在同种异体移植排斥反应开始时进行短期的BQR治疗,可以使大鼠的肝和肾同种异体移植永久存活。为了研究BQR诱导同种异体移植存活期延长的分子基础,我们在ACI到LEW肝同种异体移植模型中分析了IL-1α、IL-2、IL-2R、IL-4、IL-6、IL-10和TNF基因表达的移植内模式。我们开发了一种半定量聚合酶链反应来测量移植后不同天数的对照和BQR治疗的肝移植受者中细胞因子基因的表达。未经治疗的对照肝同种异体移植表达了所有分析的细胞因子。随着移植物排斥反应的进行,每种细胞因子转录本的稳态水平都有显著增加。在移植后第6、7和8天,用12mg/kg/天的BQR治疗肝移植受者,在给药后24小时内抑制了所有这些细胞因子的表达。细胞因子表达的早期抑制与炎性细胞向肝移植物浸润的适度但明显减少有关。IL-4、IL-6和IL-10转录本水平的降低在长期存活者(移植后30天)中持续存在。相反,在这些长期存活者中,IL-1α、IL-2和IL-2R转录本水平有显著增加。我们的结果清楚地表明,在同种异体移植排斥反应期间,细胞因子基因表达模式通过3天的BQR治疗有显著改变。细胞因子基因表达的暂时下调可能是导致肝同种异体移植存活期延长的免疫状态改变的原因。

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