Enhanced Suppression of the Xenogeneic T-Cell Response In Vitro by Xenoantigen Stimulated and Expanded Regulatory T Cells
Enhanced Suppression of the Xenogeneic T-Cell Response In Vitro by Xenoantigen Stimulated and Expanded Regulatory T Cells
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DOI：
10.1097/tp.0b013e3182a860fa
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发表时间：
2014-01-15
期刊：
影响因子：
6.2
通讯作者：
O'Connell, Philip
中科院分区：
文献类型：
--
作者：
Jin, Xi;Wang, Ya;O'Connell, Philip
背景 为了成功的异种移植，需要制定预防异种移植排斥同时最大限度地减少长期免疫抑制的策略。已知多克隆扩增的人类调节性 T 细胞 (Treg) 可抑制体内和体外的异种反应。然而，机会性感染和恶性肿瘤的风险以及需要大量Treg才能有效抑制仍然是其临床应用的缺点。本研究旨在通过异种抗原刺激扩增人类Treg，并评估其抑制异种免疫反应的有效性。方法用抗CD3/CD28珠、白细胞介素(IL)-2和雷帕霉素刺激人类CD4(+)CD25(+)CD127(lo)Treg进行多克隆扩增。 7天后，Treg通过使用或不使用抗猪SLA CII单克隆抗体的经照射的猪外周血单核细胞的多克隆刺激或异种抗原刺激的两个后续周期进一步扩增。异种抗原刺激后评估Treg表型和抑制能力。结果与多克隆刺激的对应物相比，猪异种抗原刺激的Treg保留了Treg表型，但人白细胞抗原-DR、诱导共刺激物和CD45RO的表达增加。在猪-人混合淋巴细胞反应（MLR）中，异种抗原刺激的 Treg 在应答细胞：Treg 比例较高时表现出增强的抑制能力，并分泌较高浓度的 IL-10 和 IL-35，尽管它们与同种异体或多克隆 MLR 中多克隆刺激的 Treg 具有相同的抑制作用。当 Treg 在抗猪 SLA 单克隆抗体存在下扩增并用于同一猪-人 MLR 时，其抑制能力显着降低。 结论 异种抗原刺激的 Treg 在猪-人 MLR 中显示出增强的抑制能力，很可能是通过 IL-10 介导的途径。
Background Strategies to prevent xenograft rejection while minimizing long-term immunosuppression need to be developed for successful xenotransplantaion. Polyclonally expanded human regulatory T cells (Treg) are known to suppress xenogeneic responses in vivo and in vitro. However, the risk of opportunistic infection and malignancy and the requirement for large numbers of Treg for effective suppression remain drawbacks to their clinical application. This study aimed to expand human Treg with xenoantigen stimulation and to assess their effectiveness at suppressing the xenoimmune response.Methods Human CD4(+)CD25(+)CD127(lo) Treg were stimulated with anti-CD3/CD28 beads, interleukin (IL)-2, and rapamycin for polyclonal expansion. After 7 days, Treg were further expanded with two subsequent cycles of either polyclonal stimulation or xenoantigen stimulation with irradiated porcine peripheral blood mononuclear cells with or without anti-pig SLA CII monoclonal antibody. Treg phenotype and suppressive capacity were assessed after xenoantigen stimulation.Results Porcine xenoantigen-stimulated Treg retained Treg phenotype but had an increased expression of human leukocyte antigen-DR, inducible costimulator, and CD45RO when compared with their polyclonally stimulated counterparts. In a pig-human mixed lymphocyte reaction (MLR), xenoantigen-stimulated Treg demonstrated an enhanced suppressive capacity at higher ratios of responder cells:Treg and secreted higher concentrations of IL-10 and IL-35, although they were equally suppressive as polyclonally stimulated Treg in an allogeneic or polyclonal MLR. When Treg expanded in the presence of anti-pig SLA monoclonal antibody were used in the same pig-human MLR, their suppressive capacity was reduced substantially.Conclusions Xenoantigen-stimulated Treg show enhanced suppressive capacity in the pig-human MLR most likely via an IL-10-mediated pathway.