The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
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MEK 抑制剂 Trametinib 可抑制胰岛移植后主要组织相容性抗原不匹配的排斥反应
DOI：
10.1097/txd.0000000000001045
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发表时间：
2020
影响因子：
2.3
通讯作者：
Takayuki Anazawa et al.
中科院分区：
文献类型：
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作者：
Seiichiro Tada;Takayuki Anazawa et al.
背景：潜在的副作用，如胰岛功能损害，使得传统的免疫抑制药物不适合用于胰岛移植。此外，作为单一疗法，它们不能延长胰岛移植物存活。在这里，我们研究了丝裂原活化蛋白激酶抑制剂曲美替尼的效用，并询问它是否改善急性排斥反应的移植胰岛，而不需要常规的immunosuppressants.Methods.Islets从完全主要组织相容性复合物不匹配的BALB/c小鼠通过门静脉移植到链脲佐菌素诱导的糖尿病C57 BL/6小鼠。这些小鼠接受曲美替尼或媒介物（口服）28天。从BALB/c小鼠分离的胰岛体外孵育不同浓度的曲美替尼，以确定活力和functions.Results.曲美替尼（0.1和0.3 mg/kg）延长移植物存活显着（P= 0.0007和P= 0.005，分别）相比，车辆。组织学分析显示，移植物中淋巴细胞的浸润在第7天明显受到抑制（P< 0.05）。此外，曲美替尼抑制受体中幼稚CD 4 + T细胞的功能分化。曲美替尼治疗的受者中编码炎症细胞因子白细胞介素（IL）-2、肿瘤坏死因子α和干扰素γ的mRNA表达也受到抑制（分别为P< 0.001、P< 0.05和P< 0.01）。曲美替尼还增加IL-4和IL-10的产生（分别为P< 0.05和P= 0.20）。在体外，不同浓度的曲美替尼孵育的胰岛表现出没有有害的影响方面的活力和functions.Conclusions.曲美替尼延迟胰岛移植排斥反应，抑制幼稚的CD 4 + T细胞的功能分化和调节炎症细胞因子。曲美替尼可能是异基因胰岛移植后维持免疫抑制治疗的一个有前途的候选药物。
Background.Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants.Methods.Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function.Results.Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly (P= 0.0007 and P= 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 (P< 0.05). In addition, trametinib suppressed functional differentiation of naive CD4+ T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited (P< 0.001, P< 0.05, and P< 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 (P< 0.05 and P= 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function.Conclusions.Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4+ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.