Sequential Monitoring and Stability of Ex Vivo-Expanded Autologous and Nonautologous Regulatory T Cells Following Infusion in Nonhuman Primates
Sequential Monitoring and Stability of Ex Vivo-Expanded Autologous and Nonautologous Regulatory T Cells Following Infusion in Nonhuman Primates
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DOI：
10.1111/ajt.13113
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发表时间：
2015-05-01
影响因子：
8.8
通讯作者：
Thomson, A. W.
中科院分区：
文献类型：
--
作者：
Zhang, H.;Guo, H.;Thomson, A. W.
体外扩增的食蟹猴CD 4（+）CD 25（+）CD 127（-）调节性T细胞（Treg）在Treg特异性去甲基化区域维持Foxp 3去甲基化状态，并通过三轮扩增有效抑制T细胞增殖。当将羧基荧光素琥珀酰亚胺酯-或紫色增殖染料450-标记的自体（自体）和非自体（非自体）-扩增的Treg输注到猴子中时，外周血中标记的自体Treg的数量在第一周期间迅速下降，但在正常和抗胸腺细胞球蛋白加雷帕霉素治疗（免疫抑制; IS）的动物中持续低水平至少3周。相比之下，到输注后第6天，在正常猴血液或三只IS猴中的两只的血液中不能检测到MHC错配的非自动Treg。在外周淋巴组织中，它们也比自身Treg更难检测。自体和非自体Treg在输注后早期均维持Ki 67表达。连续监测显示，与内源性Treg相比，过继转移的auto-Treg维持了类似的高水平Foxp 3和CD 25以及低水平CD 127，尽管在这些非移植受体中Foxp 3染色随着时间的推移而减少。因此，输注的离体扩增的自身Treg在非人灵长类动物的血液中比MHC错配的非自身Treg持续更长时间，并且可以在次级淋巴组织中检测到。宿主淋巴细胞耗竭和雷帕霉素给药并不能持续延长这些部位非自身调节性T细胞的持续性。
Ex vivo-expanded cynomolgus monkey CD4(+)CD25(+)CD127(-) regulatory T cells (Treg) maintained Foxp3 demethylation status at the Treg-specific demethylation region, and potently suppressed T cell proliferation through three rounds of expansion. When carboxyfluorescein succinimidyl ester- or violet proliferation dye 450-labeled autologous (auto) and nonautologous (non-auto)-expanded Treg were infused into monkeys, the number of labeled auto-Treg in peripheral blood declined rapidly during the first week, but persisted at low levels in both normal and anti-thymocyte globulin plus rapamycin-treated (immunosuppressed; IS) animals for at least 3 weeks. By contrast, MHC-mismatched non-auto-Treg could not be detected in normal monkey blood or in blood of two out of the three IS monkeys by day 6 postinfusion. They were also more difficult to detect than auto-Treg in peripheral lymphoid tissue. Both auto- and non-auto-Treg maintained Ki67 expression early after infusion. Sequential monitoring revealed that adoptively transferred auto-Treg maintained similarly high levels of Foxp3 and CD25 and low CD127 compared with endogenous Treg, although Foxp3 staining diminished over time in these nontransplanted recipients. Thus, infused ex vivo-expanded auto-Treg persist longer than MHC-mismatched non-auto-Treg in blood of nonhuman primates and can be detected in secondary lymphoid tissue. Host lymphodepletion and rapamycin administration did not consistently prolong the persistence of non-auto-Treg in these sites.