Human islet function is not impaired by the sphingosine-1-phosphate receptor modulator FTY720
Human islet function is not impaired by the sphingosine-1-phosphate receptor modulator FTY720
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DOI：
10.1111/j.1600-6143.2007.01880.x
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发表时间：
2007-08-01
影响因子：
8.8
通讯作者：
Shapiro, A. M. James
中科院分区：
文献类型：
--
作者：
Truong, W.;Emamaullee, J. A.;Shapiro, A. M. James
目前，临床1型糖尿病的胰岛移植需要强效的免疫抑制药物，这将该手术限制在最严重的疾病形式，并且许多药物直接对β细胞有毒。一类称为鞘氨醇-1-磷酸受体调节剂的化合物已在移植中进行了探索，并显示出在多发性硬化症和其他自身免疫性疾病中非常有效。虽然FTY 720是这类药物中的第一种药物，但在移植初期可能不会向前发展，但这类药物需要进行详细的研究，以评估对人类β细胞功能和存活的直接影响。我们着手通过研究葡萄糖刺激的胰岛素和细胞凋亡来评估FTY 720对体外人胰岛的影响;在体内，移植到患有化学诱导糖尿病的免疫缺陷小鼠体内后，通过检查血糖水平、口服葡萄糖耐量试验和刺激的人C肽在50天的随访期内。我们的数据表明，无论是在体外，也不是在体内人体胰岛功能受损FTY 720曝光。由于FTY 720在体外或体内对人胰岛功能没有不利影响，新兴的S1 PR调节剂可能被证明是临床胰岛移植中有用的替代品，因为缺乏致糖尿病性和有效的免疫保护。
Clinical islet transplantation for type 1 diabetes mellitus currently requires potent immunosuppressive drugs, which limits the procedure to the most severe forms of the disease, and many of the drugs are directly beta-cell toxic. A class of compounds called sphingosine-1-phosphate receptor modulators has been explored in transplantation and shown to be highly effective in multiple sclerosis and other autoimmune conditions. While FTY720, the first drug in this class, may not move forward initially in transplantation, this class requires detailed investigation to assess direct impact upon human beta-cell function and survival. We set out to evaluate the effects of FTY720 on human islets in vitro by investigating glucose-stimulated insulin and apoptosis; and in vivo, after transplantation into immunodeficient mice with chemically induced diabetes, by examining blood glucose levels, oral glucose tolerance tests and stimulated human C-peptide over a 50-day follow-up period. Our data showed that neither in vitro, nor in vivo human islet function was impaired by FTY720 exposure. Since FTY720 demonstrated no detrimental effects on human islet function in vitro or in vivo, emerging S1PR modulators may prove to be useful adjuncts in clinical islet transplantation through lack of diabetogenicity and potent immunological protection.