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. 2022 Apr 20;42(4):598-603.
doi: 10.12122/j.issn.1673-4254.2022.04.17.

[The dual mTORC1/2 inhibitor AZD2014 inhibits acute graft rejection in a rat liver transplantation model]

[Article in Chinese]
H Liao  1 , Y Wang  1 , X Xu  1 , C Zhou  1 , J Zhang  1 , K Zhong  1 , D Yang  2
Affiliations

[The dual mTORC1/2 inhibitor AZD2014 inhibits acute graft rejection in a rat liver transplantation model]

[Article in Chinese]
H Liao et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To investigate the inhibitory effect of AZD2014, a dual mTORC1/2 inhibitor, against acute graft rejection in a rat model of allogeneic liver transplantation.

Methods: Liver transplantation from Lewis rat to recipient BN rat (a donor-recipient combination that was prone to induce acute graft rejection) was performed using Kamada's two-cuff technique. The recipient BN rats were randomized into 2 groups for treatment with daily intraperitoneal injection of AZD2014 (5 mg/kg, n=4) or vehicle (2.5 mL/kg, n=4) for 14 consecutive days, starting from the first day after the transplantation. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels of the rats were measured 3 days before and at 1, 3, 5, 7, 10, and 14 days after the transplantation, and the survival time of the rats within 14 days were recorded. Immunohistochemical staining was used to examine the expressions of CD3 and Foxp3 in the liver graft, and acute graft rejection was assessed using HE staining based on the Banff schema.

Results: Three rats in the control group died within 14 days after the surgery, while no death occurred in the AZD2014 group, demonstrating a significantly longer survival time of the rats in AZD2014 group (χ2=4.213, P=0.04). Serum ALT, AST and TBIL levels in the control group increased progressively after the surgery and were all significantly higher than those in AZD2014 group at the same time point (P < 0.05). Pathological examination revealed significantly worse liver graft rejection in the control group than in AZD2014 group based on assessment of the rejection index (P < 0.01); the rats in the control group showed more serious T lymphocyte infiltration and significantly fewer Treg cells in the liver graft than those in AZD2014 group (P < 0.01).

Conclusions: AZD2014 can effectively inhibit acute graft rejection in rats with allogeneic liver transplantation.

目的: 在同种异基因大鼠肝移植模型中验证AZD2014是否具有抑制肝移植术后急性排斥反应的作用。

方法: 采用Kamada提出的“二袖套”法建立Lewis→BN同种异基因大鼠肝移植急性排斥反应模型，随机分成对照组和AZD2014组，各4只。AZD2014组腹腔内注射AZD2014药物，5 mg/kg，1次/d；对照组腹腔内注射药物溶剂2.5 mL/kg，1次/d。不同时间点取外周血检测肝功能（丙氨酸氨基转移酶、天门冬氨酸氨基转移酶和总胆红素）。记录生存时间，进行生存分析。移植肝脏行免疫组化检测CD3和Foxp3的表达水平，评估T淋巴细胞和Treg淋巴细胞浸润的程度；移植肝脏行HE染色，采用Banff方案评估肝移植术后排斥反应的严重程度。

结果: 对照组在术后14 d内有3/4的大鼠死亡，而AZD2014组在术后14 d内无大鼠死亡，AZD2014组与对照组相比生存时间明显延长（χ2=4.213，P=0.040）。对照组血清中ALT、AST和TBIL进行性升高，上述指标均高于同时间AZD2014组（P < 0.05）。病理检查显示对照组移植肝内排斥反应明显重于AZD2014组（排斥指数P < 0.01），对照组中T淋巴细胞（CD3阳性）浸润相较于AZD2014组更为严重（P < 0.01），而Treg细胞（Foxp3阳性）明显少于AZD2014组（P < 0.01）。

结论: 双mTORC1/2抑制剂AZD2014可以有效地抑制同种异基因大鼠肝移植术后的急性排斥反应。

Keywords: AZD2014; graft rejection; liver transplantation; mTOR inhibitor.

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Figures

图 1
图 1
肝移植术后对照组和AZD2014组的生存分析 Survival analysis of the rats treated with AZD2014 or vehicle after liver transplantation (χ2= 4.213, P=0.040).
图 2
图 2
肝移植术后2周内各组血清ALT、AST和TBIL的水平 Changes of serum ALT (A), AST (B) and TBIL (C) levels in the two groups within 14 days after liver transplantation.
图 3
图 3
肝移植术后移植肝的HE染色 HE staining of the liver graft in the two groups. A: Inflammatory cell infiltration in the control group. B: The complete hepatic lobule system in the control group. C: Inflammatory cell infiltration in the control group. D: Inflammatory cell infiltration in AZD2014 group. E: Complete hepatic lobule system in AZD2014 group. F: Inflammatory cell infiltration in AZD2014 group.
图 4
图 4
肝移植术后移植肝的排斥反应指数评分 Rejection activity index of the liver grafts in the two groups (*P < 0.01 vs control group).
图 5
图 5
免疫组化检测移植肝脏中CD3分子 Immunohistochemical staining of CD3 in the liver graft. A: Control group. B: AZD2014 group. C: Number of CD3+ cells (*P < 0.01 vs control group).
图 6
图 6
免疫组化检测移植肝脏中Foxp3分子 Immunohistochemical staining of Foxp3 in the liver grafts in the two groups. A: Control group. B: AZD2014 group. C: Number of Foxp3+ cells (*P < 0.01 vs control group).
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