Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA.
Am J Transplant. 2014 Jan;14(1):59-69. doi: 10.1111/ajt.12526.
De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.
器官移植后新出现的供体特异性抗体 (DSA) 可促进抗体介导的排斥反应 (AMR)，并导致移植物晚期丢失。此前，我们证明，使用抗 CD3 免疫毒素联合他克莫司和阿利昔单抗（AMR 方案）进行耗竭可在非人类灵长类动物肾移植模型中可靠地诱导早期 DSA 产生和 AMR。5 只动物被分配为阳性 AMR 对照组，4 只接受了额外的贝利尤单抗，4 只接受了额外的抗 CD40 mAb（2C10R4）。值得注意的是，额外使用贝利尤单抗或 2C10R4 治疗可完全抑制早期新出现的 DSA 产生。与此一致的是，阳性对照动物的外周 IgM(+) B 细胞减少，而贝利尤单抗和 2C10R4 加药组则保持了主要的 IgM(+) B 细胞群体，这可能表明同种型转换减少。中央记忆 T 细胞（CD4(+) CD28(+) CD95(+））和 PD-1(hi) CD4(+) T 细胞在贝利尤单抗和 2C10R4 加药组中均减少。在分析原位生发中心 (GC) 反应时，淋巴结进一步显示 B 细胞克隆扩增、GC 滤泡辅助 T (Tfh) 细胞和 GC 内 IL-21 产生减少，这与额外使用贝利尤单抗或 2C10R4 治疗有关。在这里，我们提供的证据表明，贝利尤单抗和 2C10R4 通过调节 Tfh 细胞选择性抑制体液反应，并在该非人类灵长类动物模型中预防 AMR。
