KRP-203 Is a Desirable Immunomodulator for Islet Allotransplantation.
KRP-203 Is a Desirable Immunomodulator for Islet Allotransplantation.
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DOI：
10.1097/tp.0000000000003870
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发表时间：
2022-05-01
期刊：
影响因子：
6.2
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中科院分区：
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作者：
目前的标准免疫抑制方案，钙调磷酸酶抑制剂，对胰岛移植物有致糖尿病和抗血管化作用。KRP-203是一种1-磷酸鞘氨醇功能性拮抗剂，通过淋巴细胞隔离发挥其免疫调节功能。然而，这种拮抗剂对胰岛的影响尚不清楚。我们研究了KRP-203对胰岛功能和血管化的影响，并寻求一种无钙调神经磷酸酶的胰岛同种异体移植方案。将KRP-203给药于小鼠14 d，然后通过血糖水平和葡萄糖耐量试验评价致糖尿病作用。静态葡萄糖刺激，呼吸指数和胰岛素/DNA使用分离的胰岛进行了检查。用多光子激光扫描显微镜评价胰岛新生血管形成。在用单独的KRP-203、单独的西罗莫司或两者组合进行胰岛同种异体移植后，通过血糖水平和免疫组织化学分析来评估移植物存活。还进行了混合淋巴细胞反应以研究KRP-203和西罗莫司的免疫学特性。在对照组和KRP-203组之间没有观察到血糖水平或葡萄糖耐量的显著差异。胰岛分离后的功能测定也相当。多光子激光扫描显微镜显示KRP-203对胰岛新生血管无抑制作用。尽管KRP-203单药治疗有效抑制了同种异体排斥反应（44%），但联合治疗在大多数移植小鼠中预防了排斥反应（83%）。KRP-203是胰岛移植的理想免疫调节剂，因为其保留了内分泌功能且不干扰胰岛新生血管形成。KRP-203与低剂量西罗莫司的组合可能是有希望的，作为胰岛同种异体移植的无钙调神经磷酸酶方案。
The current standard immunosuppressive regimens, calcineurin inhibitors, have diabetogenic and anti-vascularization effects on islet grafts. KRP-203, a sphingosine-1-phosphate functional antagonist, exerts its immunomodulatory function through lymphocyte sequestration. However, the effect of this antagonist on islets is unclear. We examined the effect of KRP-203 on the islet function and vascularization and sought a calcineurin-free regimen for islet allotransplantation. KRP-203 was administered for 14 d to mice, then diabetogenic effect was evaluated by blood glucose levels and a glucose tolerance test. Static glucose stimulation, the breathing index, and insulin/DNA were examined using isolated islets. Islet neovascularization was evaluated using a multiphoton laser scanning microscope. After islet allotransplantation with either KRP-203 alone, sirolimus alone, or both in combination, the graft survival was evaluated by blood glucose levels and immunohistochemical analyses. A mixed lymphocyte reaction was also performed to investigate the immunologic characteristics of KRP-203 and sirolimus. No significant differences in the blood glucose levels or glucose tolerance were observed between the control and KRP-203 groups. Functional assays after islet isolation were also comparable. The multiphoton laser scanning microscope showed no inhibitory effect of KRP-203 on islet neovascularization. Although allogeneic rejection was effectively inhibited by KRP-203 monotherapy (44%), combination therapy prevented rejection in most transplanted mice (83%). KRP-203 is a desirable immunomodulator for islet transplantation because of the preservation of the endocrine function and lack of interference with islet neovascularization. The combination of KRP-203 with low-dose sirolimus may be promising as a calcineurin-free regimen for islet allotransplantation.