CTLA4-Ig and anti-CD4O ligand prevent renal allograft rejection in primates
CTLA4-Ig and anti-CD4O ligand prevent renal allograft rejection in primates
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DOI：
10.1073/pnas.94.16.8789
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发表时间：
1997-08-05
影响因子：
11.1
通讯作者：
Knechtle, SJ
中科院分区：
文献类型：
--
作者：
Kirk, AD;Harlan, DM;Knechtle, SJ
已经显示使用B7特异性融合蛋白CTLA 4-IG选择性抑制T细胞共刺激诱导啮齿动物中的长期同种异体移植物存活。已经显示在啮齿动物中阻止CD 40和其基于T细胞的配体CD 154（CD 40 L）之间相互作用的抗体与CTLA 4-IG协同作用，因此，有人假设这些药物可能能够诱导灵长类动物对同种异体移植组织的长期接受。为了在相关的临床前模型中检验这一假设，在恒河猴中测试了CTLA 4-IG和CD 40 L特异性单克隆抗体5C 8。这两种药物都有效地抑制恒河猴混合淋巴细胞反应，但联合使用比单独使用任何一种药物的效果高100倍。将肾同种异体移植物移植到肾切除的恒河猴中，这些恒河猴显示在主要组织相容性复合物I类和II类基因座上是不同的，对照组动物在5-8天内发生排斥反应，短暂诱导剂量的CTLA 4-IG或单独的5C 8显著延长了无排斥反应的存活时间（20-98天），接受两种药物治疗的4只动物中有2只出现了延长的（>150天）无排斥的同种异体移植物存活率。两只单独用5C 8治疗的动物和一只用5C 8和CTLA 4-IG两者治疗的动物经历了晚期的、经活检证实的排斥，但其诱导方案的重复过程成功地恢复了正常的移植物功能，两种药物均不影响外周T细胞或B细胞计数，在治疗期间没有临床明显的副作用或排斥反应。我们得出结论，CTLA 4-IG和5C 8都可以预防和逆转急性移植物排斥反应，显著延长灵长类动物中主要组织相容性复合物不匹配的肾同种异体移植物的存活，而不需要慢性免疫抑制。
Selective inhibition of T cell costimulation using the B7-specific fusion protein CTLA4-Ig has been shown to induce long-term allograft survival in rodents, Antibodies preventing the interaction between CD40 and its T cell-based ligand CD154 (CD40L) have been shown in rodents to act synergistically with CTLA4-Ig, It has thus been hypothesized that these agents might be capable of inducing long-term acceptance of allografted tissues in primates. To test this hypothesis in a relevant preclinical model, CTLA4-Ig and the CD40L-specific monoclonal antibody 5C8 were tested in rhesus monkeys, Both agents effectively inhibited rhesus mixed lymphocyte reactions, but the combination was 100 times more effective than either drug alone, Renal allografts were transplanted into nephectomized rhesus monkeys shown to be disparate at major histocompatibility complex class I and class II loci, Control animals rejected in 5-8 days, Brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-free survival (20-98 days), Two of four animals treated with both agents experienced extended (>150 days) rejection-free allograft survival, Two animals treated with 5C8 alone and one animal treated with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection, but a repeat course of their induction regimen successfully restored normal graft function, Neither drug affected peripheral T cell or B cell counts, There were no clinically evident side effects or rejections during treatment, We conclude that CTLA4-Ig and 5C8 can both prevent and reverse acute allograft rejection, significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.