Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154
Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154
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DOI：
10.1073/pnas.96.14.8132
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发表时间：
1999-07-06
影响因子：
11.1
通讯作者：
Ricordi, C
中科院分区：
文献类型：
--
作者：
Kenyon, NS;Chatzipetrou, M;Ricordi, C
据报道，抗 CD154 治疗对自身免疫、同种异体反应性以及巨噬细胞和内皮细胞介导的炎症事件的影响表明，它可能是预防肝内胰岛同种异体移植失败的理想药物。这一假设在 MHC 不匹配的恒河猴中得到了检验。在接受抗 CD154 (hu5c8) 诱导加每月维持治疗（术后天数 >125、>246、>266、>405、>419、>476）治疗的 6 名受者中，有 6 名受者移植了足够数量的活胰岛，从而实现了植入和胰岛素独立。抗 CD154 (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，移植后 100 天后观察到移植功能持续改善，这是通过响应静脉注射葡萄糖的第一阶段胰岛素释放来确定的。尚未观察到毒性或感染性并发症的证据。所有接受抗 CD154 治疗的受体在混合淋巴细胞反应中都对供体细胞无反应。此外，三只猴子现已停止治疗（停止抗CD154治疗> 113天、> 67天和> 54天），持续存在胰岛素依赖性和供体特异性混合淋巴细胞反应低反应性。与之前测试的所有策略形成鲜明对比的是，在抗 CD154 (hu5c8) 单一疗法的覆盖下移植足够数量的功能性胰岛始终能够在这种高度相关的临床前模型中实现同种异体胰岛移植和长期的胰岛素独立性。
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). Anti-CD154 (hu5c8) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement ingraft 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 nonresponsive 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.