Mita Atsuyoshi, Ricordi Camillo, Miki Atsushi, Barker Scott, Haertter Ross, Hashikura Yasuhiko, Miyagawa Shin-Ichi, Burke George W, Inverardi Luca, Ichii Hirohito
Cell Transplant Center, Diabetes Research Institute, Miami, FL, USA.
Transplantation. 2008 Jul 15;86(1):46-53. doi: 10.1097/TP.0b013e31817c79c0.
Sirolimus plays a critical role in facilitating steroid-free immunosuppression, in conjunction with low dose tacrolimus, in current islet transplantation. Although several studies have investigated the effects of sirolimus on islet cells, conflicting results have been reported. In this study, we assessed the effects of sirolimus supplementation in culture media on human islet preparations, focusing on the anti-proinflammatory aspects.
Human islet preparations were divided into four groups: pure (purity >90%) sirolimus (30 ng/mL); pure control (0 ng/mL); impure (purity 40%-60%) sirolimus; and impure control. All groups were cultured for 3 days and assessed regarding glucose stimulated insulin release, fractional beta-cell viability, beta-cell, and macrophage content. Cytokine and chemokine production from islet preparations and sorted pancreatic ductal cells were also examined.
Stimulated insulin release in the impure sirolimus group was significantly increased (P=0.024), as previously reported. Although fractional beta-cell viability showed no significant differences, beta-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-alpha, interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1beta production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-alpha and macrophage inflammatory protein-1beta production from sorted ductal cells significantly decreased in the sirolimus group (P<0.05). The number of macrophages contained in islet preparations significantly decreased in the impure sirolimus group when compared with the impure control group (P<0.05).
Sirolimus improved not only stimulated insulin release, but also beta-cell survival during culture. The antiinflammatory effects of sirolimus also appear beneficial to islet cells in culture and may be a useful strategy in improving islet transplantation outcomes.
在当前的胰岛移植中，西罗莫司与低剂量他克莫司联合使用，在促进无类固醇免疫抑制方面发挥着关键作用。尽管有几项研究调查了西罗莫司对胰岛细胞的影响，但报道的结果相互矛盾。在本研究中，我们评估了在培养基中添加西罗莫司对人胰岛制剂的影响，重点关注抗炎方面。
将人胰岛制剂分为四组：纯（纯度>90%）西罗莫司（30 ng/mL）；纯对照组（0 ng/mL）；不纯（纯度40%-60%）西罗莫司；和不纯对照组。所有组均培养3天，并评估葡萄糖刺激的胰岛素释放、β细胞存活率、β细胞和巨噬细胞含量。还检测了胰岛制剂和分选的胰腺导管细胞产生的细胞因子和趋化因子。
如先前报道，不纯西罗莫司组的刺激胰岛素释放显著增加（P=0.024）。尽管β细胞存活率没有显著差异，但与不纯对照组相比，不纯西罗莫司组在培养期间的β细胞存活率显著增加（P=0.015）。不纯西罗莫司组产生的肿瘤坏死因子-α、白细胞介素-1β、单核细胞趋化蛋白-1和巨噬细胞炎性蛋白-1β显著减少（P<0.05）。此外，西罗莫司组分选的导管细胞产生的肿瘤坏死因子-α和巨噬细胞炎性蛋白-1β显著减少（P<0.05）。与不纯对照组相比，不纯西罗莫司组胰岛制剂中所含巨噬细胞的数量显著减少（P<0.05）。
西罗莫司不仅改善了刺激胰岛素释放，还提高了培养期间的β细胞存活率。西罗莫司的抗炎作用似乎对培养中的胰岛细胞也有益，可能是改善胰岛移植结果的一种有用策略。
