Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response
Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response
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DOI：
10.1038/s41598-020-69009-8
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发表时间：
2020-07
影响因子：
4.6
通讯作者：
K. Yamane;T. Anazawa;S. Tada;N. Fujimoto;K. Inoguchi;Norio Emoto;K. Nagai;T. Masui;H. Okajima;K. Takaori;S. Sumi;S. Uemoto
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文献类型：
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作者：
K. Yamane;T. Anazawa;S. Tada;N. Fujimoto;K. Inoguchi;Norio Emoto;K. Nagai;T. Masui;H. Okajima;K. Takaori;S. Sumi;S. Uemoto
在细胞移植（即胰岛移植）之前的体外培养期能够进行细胞修饰，因此是有利的。然而，胰岛预处理方法尚未得到充分探索。在这里，我们提出了一个简单的方法，胰岛预处理，使用抗生素丝裂霉素C（MMC），它具有抗肿瘤活性，以减少胰岛免疫原性和防止促炎事件在门静脉内胰岛移植模型。新鲜分离的小鼠胰岛经10 μg/mLMMC处理30 min后，培养20 h，移植于同基因或异基因糖尿病小鼠受体肝脏。在同种异体模型中，MMC预处理显著延长移植物存活，而不需要免疫抑制剂。在体外，MMC治疗抑制胰岛移植物中促炎细胞因子的表达，而免疫组化研究显示，相对于未处理的同种异体移植物，MMC治疗的同种异体移植物中的炎性细胞浸润受到抑制。此外，MMC预处理显着抑制促炎细胞因子的mRNA表达到移植部位，并诱导分化的调节性T细胞的能力，抑制CD 4 +T细胞介导的免疫反应。总之，在门静脉内胰岛移植模型中，MMC预处理胰岛通过抑制促炎事件和诱导潜在的调节性淋巴细胞延长移植物存活。
The in vitro culture period prior to cell transplantation (i.e. pancreatic islet transplantation) enables cell modification and is thus advantageous. However, the islet preconditioning method has not been fully explored. Here we present a simple approach for islet preconditioning that uses the antibiotic mitomycin C (MMC), which has antitumor activity, to reduce islet immunogenicity and prevent proinflammatory events in an intraportal islet transplantation model. Freshly isolated mice islets were treated for 30 min with 10 μg/mL MMC or not, cultured for 20 h and transplanted into the livers of syngeneic or allogeneic diabetic mouse recipients. In the allogeneic model, MMC preconditioning significantly prolonged graft survival without requiring immunosuppressants. In vitro, MMC treatment suppressed the expression of proinflammatory cytokines in islet allografts, while immunohistochemical studies revealed the suppression of inflammatory cell infiltration into MMC-treated allografts relative to untreated allografts. Furthermore, MMC preconditioning significantly suppressed the mRNA expression of proinflammatory cytokines into the transplant site and induced the differentiation of regulatory T cells with the ability to suppress CD4+T cell-mediated immune responses. In conclusion, islet preconditioning with MMC prolonged graft survival in an intraportal islet transplantation model by suppressing proinflammatory events and inducing potentially regulatory lymphocytes.