Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model
Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model
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DOI：
10.1097/01.tp.0000116392.72152.75
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发表时间：
2004-03-27
期刊：
影响因子：
6.2
通讯作者：
Knechtle, SJ
中科院分区：
文献类型：
--
作者：
Kanmaz, T;Fechner, JH;Knechtle, SJ
背景。本研究评估了新型人抗人 CD154 单克隆抗体 ABI793 在恒河猴中的安全性和有效性。方法。近交系恒河猴被用于来自主要组织相容性复合物不匹配供体的肾移植。七名接受者接受了 ABI793 治疗，六名未经治疗的接受者用作对照。通过尿量、血清肌酐和肾活检监测移植物功能。移植前和移植后定期进行外周血淋巴细胞表型分析和混合淋巴细胞反应。在处死时测量抗供体主要组织相容性复合物 I 类抗体水平。结果。与对照组相比，治疗组的猴子表现出更长的移植存活率。术后第 13 天，一只猴子因漏尿而被处死。三只猴子因急性排斥反应（第 44、149 和 158 天）而被处死。两只猴子因慢性主动排斥反应（第 154 天和第 221 天）而被处死。在第 139 天，在没有排斥的情况下处死一只猴子，以观察 ABI793 在没有排斥的情况下的效果。 ABI793没有明显的临床副作用，但在两只猴子中观察到微观血栓栓塞变化。所有猴子的淋巴细胞亚群均保持不变。移植后6周混合淋巴细胞反应显示非特异性抑制。慢性主动排斥反应的猴子表现出较强的同种抗体反应。结论。 ABI793 可延长恒河猴肾同种异体移植物的存活时间。然而，停止抗CD154治疗后，可能会发生血栓栓塞并发症，并且可能会发展为慢性同种异体移植肾病。
Background. This study assesses the safety and efficacy of the novel human anti-human CD154 monoclonal antibody ABI793 in rhesus monkeys.Methods. Outbred rhesus monkeys were used for renal transplantation from major histocompatibility complex-mismatched donors. Seven recipients were treated with ABI793, and six untreated recipients were used as controls. Graft function was monitored by urine output, serum creatinine, and renal biopsy. Phenotypic analysis of peripheral blood lymphocytes and mixed lymphocyte reaction were performed before transplantation and periodically after transplantation. Anti-donor major histocompatibility complex class I antibody levels were measured at the time of sacrifice.Results. Monkeys in the treated group demonstrated prolonged graft survival compared with controls. One monkey was sacrificed because of a urine leak on postoperative day 13. Three monkeys were sacrificed because of acute rejection (days 44, 149, and 158). Two monkeys were sacrificed because of chronic active rejection (days 154 and 221). One monkey was sacrificed on day 139 without rejection to observe the effects of ABI793 in the absence of rejection. There were no obvious clinical side effects of ABI793, but microscopic thromboembolic changes were observed in two monkeys. Lymphocyte subsets remained unaltered in all monkeys. Mixed lymphocyte reaction showed nonspecific suppression 6 weeks after transplantation. The monkeys with chronic active rejection showed relatively strong alloantibody responses.Conclusions. ABI793 induces prolonged renal allograft survival in rhesus monkeys. Nevertheless, thromboembolic complications may occur and chronic allograft nephropathy may develop after anti-CD154 treatment is discontinued.