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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154
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Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154

机译：人源化抗CD154治疗恒河猴肝内胰岛移植的长期存活和功能

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摘要

Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inflammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHC-mismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (post-operative day > 125, >246, >266, >405, >419, >476). AntiCD154 (hu5c8) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement in graft function, as determined by first phase insulin release in response to intravenous glucose, was observed after the first 100 days post-transplant. No evidence of toxicity or infectious complications has been observed. All recipients treated with anti-CD154 became specifically non-responsive to donor cells in mixed lymphocyte reactions. Furthermore, three monkeys are now off therapy (>113, >67, and >54 days off anti-CD154), with continued insulin independence and donor-specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.
机译：抗CD154治疗对巨噬细胞和内皮细胞介导的自身免疫性，同种反应性和炎症事件的报道影响表明，它可能是预防肝内胰岛同种异体移植失败的理想药物。在MHC不匹配的恒河猴中测试了该假设。移植足够数量的活胰岛导致接受抗CD154（hu5c8）诱导和每月维持治疗的六位接受者中有六位接受了移植和胰岛素独立治疗（术后一天> 125，> 246，> 266，> 405，> 419，> 476）。 AntiCD154（hu5c8）对胰岛细胞功能没有抑制作用。对于随访超过100天的猴子，在移植后的头100天后观察到移植物功能的持续改善，这是通过响应静脉葡萄糖的第一阶段胰岛素释放确定的。没有观察到毒性或感染性并发症的证据。在混合淋巴细胞反应中，所有接受抗CD154治疗的受体都对供体细胞无反应。此外，三只猴子现已停用治疗（抗CD154停用> 113天，> 67天和> 54天），持续存在胰岛素独立性和供体特异性混合淋巴细胞反应低反应性。与以前测试过的所有策略形成鲜明对比的是，在这种高度相关的临床前模型中，在抗CD154（hu5c8）单药治疗的覆盖下移植足够数量的功能性胰岛始终可以实现同种异体胰岛移植和长期胰岛素独立性。

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