Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production
Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production
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DOI：
10.1097/00007890-200206150-00019
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发表时间：
2002-06-15
期刊：
影响因子：
6.2
通讯作者：
Kobayashi, M
中科院分区：
文献类型：
--
作者：
Jiang, HS;Wynn, C;Kobayashi, M
背景。临床移植积累的证据表明，即使高剂量的抗排斥挽救治疗失败，基于他克莫司的治疗也可以逆转接受基于环孢素（CsA）的免疫抑制治疗的患者正在进行的同种异体移植排斥反应。这一证据促使我们研究这两种具有体外机制的化合物在正在进行的同种异体移植排斥过程中调节原位细胞和分子事件的能力是否有所不同。当对Lewis大鼠口服给药10天（第0-9天）时，他克莫司（3.2 mg/kg/天）和CsA（10 mg/kg/天）的等效有效剂量被预先确定并定义为该药物诱导布朗挪威大鼠同种异体心脏移植物类似存活的能力，并同等抑制移植物内白细胞介素（IL）-2 mRNA表达。为了研究每种药物挽救正在进行的同种异体移植排斥的能力，布朗挪威大鼠心脏移植物的Lewis受体在移植后的前5天内没有接受治疗。然后以等效有效剂量给予他克莫司或 CsA，持续 10 天（第 5-14 天）。通过逆转录酶-聚合酶链式反应、实时定量聚合酶链式反应、ELISA 和免疫组织学对第 3、5、7 和 10 天收获的心脏移植物和血液样本进行分析。结果。发现他克莫司可以挽救正在进行的同种异体移植排斥反应，但同等剂量的 CsA 则不能挽救（中位生存时间：未经治疗，6 天；他克莫司，18 天；CsA，7 天）。通过减少细胞毒性因子（包括颗粒酶 B 和穿孔素 1）释放，显着抑制局部移植物内 IL-10 mRNA 表达和血清蛋白产生，并显着下调功能性 CD8(+) T 和 NHR-P1a(+) 自然杀伤细胞局部浸润，发现与他克莫司治疗相关，但与 CsA 治疗无关。然而，两种药物对其他免疫细胞（CD4（+）T细胞、ED2（+）巨噬细胞）和细胞因子（IL-1β、IL-2、IL-4、IL-6、IL-12、干扰素-γ、转化生长因子-β和肿瘤坏死因子-α）的抑制水平几乎相同。 CsA 无法克服正在进行的同种异体移植排斥，可以通过在移植后第 5 天和第 6 天用中和性抗 IL-10 抗体共同治疗受体来挽救：单独的抗 IL-10 抗体没有显示出这样的效果。结论。抑制 IL-10 的产生是他克莫司逆转正在进行的同种异体移植排斥的能力的关键因素。
Background. Accumulated evidence from clinical transplantation has suggested that tacrolimus-based treatment can reverse ongoing allograft rejection in patients treated with cyclosporine (CsA)-based immunosuppression, even when a high dose of antirejection rescue therapy has failed. This evidence prompted us to investigate whether these two compounds, which share an in vitro mechanism, would differ in their abilities to regulate in situ cellular and molecular events during ongoing allograft rejection.Methods. The equivalent effective doses of tacrolimus (3.2 mg/kg/day) and CsA (10 mg/kg/day), when administered orally to Lewis rats for 10 days (day 0-9), were predetermined and defined as the ability of the drug to induce a similar survival of Brown Norway rat heart allografts with an equal suppression of intragraft interleukin (IL)-2 mRNA expression. To investigate the ability of each drug to rescue ongoing allograft rejection, Lewis recipients of Brown Norway rat heart grafts were left untreated for the first 5 days after transplantation. Tacrolimus or CsA was then administered at the equivalent effective dose for 10 days (days 5-14). Heart grafts and blood samples, harvested on days 3, 5, 7, and 10, were analyzed by reverse transcriptase-polymerase chain reaction, real-time quantitative polymerase chain reaction, ELISA, and immunohistology.Results. Ongoing allograft rejection was found to be rescued by tacrolimus but not by CsA at the equivalent dose (median survival time: untreated, 6 days; tacrolimus, 18 days; and CsA, 7 days). A significant suppression of local intragraft IL-10 mRNA expression and serum protein production along with a dramatic down-regulation of functional CD8(+) T and NHR-P1a(+) natural killer cell local infiltration by means of decreased of cytotoxic factor release, including granzyme B and perforin 1, was found to be associated with tacrolimus but not CsA treatment. However, both drugs inhibited other immune cells (CD4(+) T cell, ED2(+) macrophage) and cytokines (IL-1beta, IL-2, IL-4, IL-6, IL-12, interferon-gamma, transforming growth factor-beta, and tumor necrosis factor-alpha) at almost the same levels. The inability of CsA to overcome ongoing allograft rejection could be rescued by cotreating recipients with neutralizing anti-IL-10 antibody on day 5;and day 6 after transplantation: anti-IL-10 antibody alone did not show such an effect.Conclusions. Inhibition of IL-10 production is a critical factor in the ability of tacrolimus to reverse ongoing allograft rejection.