Brandhorst Daniel, Brandhorst Heide, Acreman Samuel, Abraham Anju, Johnson Paul R V
Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Oxford Consortium for Islet Transplantation, Oxford Centre for Diabetes, Endocrinology, and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, OX3 7LE, UK.
J Inflamm Res. 2021 Feb 26;14:599-610. doi: 10.2147/JIR.S294663. eCollection 2021.
Most islet transplant groups worldwide routinely use the TNFα inhibitor Etanercept in their peri-transplant protocols. Surprisingly, there have been no published dose-response studies on the effects of Etanercept on human islets. Our study aimed to address this by treating cultured human islets with increasing concentrations of Etanercept.
Isolated human islets were cultured for 3-4 days in normoxic (21% oxygen) or in hypoxic (2% oxygen) atmosphere using Etanercept dissolved in a range of 2.5-40 µg/mL prior to islet characterisation.
In normoxic atmosphere, it was found that 5 µg/mL is the most efficient dose to preserve islet morphological and functional integrity during culture. Increasing the dose to 10 µg/mL or more resulted in detrimental effects with respect to viability and glucose-stimulated insulin release. When human islets were cultured for 3 to 4 days in clinically relevant hypoxia and treated with 5 µg/mL Etanercept, post-culture islet survival ( < 0.001) and in vitro function ( < 0.01) were significantly improved. This correlated with a substantially reduced cytokine production ( < 0.05), improved mitochondrial function ( < 0.01), and reduced production of reactive oxygen species ( < 0.001) in hypoxia-exposed islets.
These findings suggest that the therapeutic window of Etanercept is very narrow and that this should be considered when optimising the dosage and route of Etanercept administration in islet-transplant recipients or when designing novel drug-delivering islet scaffolds.
全球大多数胰岛移植组在其移植围手术期方案中常规使用肿瘤坏死因子α（TNFα）抑制剂依那西普。令人惊讶的是，尚未有关于依那西普对人胰岛作用的剂量反应研究发表。我们的研究旨在通过用浓度递增的依那西普处理培养的人胰岛来解决这一问题。
在胰岛特性分析之前，将分离的人胰岛在常氧（21%氧气）或低氧（2%氧气）环境中培养3 - 4天，使用溶解在2.5 - 40µg/mL范围内的依那西普。
在常氧环境中，发现5µg/mL是培养期间保持胰岛形态和功能完整性的最有效剂量。将剂量增加到10µg/mL或更高会对活力和葡萄糖刺激的胰岛素释放产生有害影响。当人胰岛在临床相关的低氧环境中培养3至4天并用5µg/mL依那西普处理时，培养后胰岛存活率（<0.001）和体外功能（<0.01）显著改善。这与低氧暴露胰岛中细胞因子产生显著减少（<0.05）、线粒体功能改善（<0.01）以及活性氧产生减少（<0.001）相关。
这些发现表明依那西普的治疗窗非常窄，在优化胰岛移植受者中依那西普的给药剂量和途径或设计新型药物递送胰岛支架时应考虑这一点。
