Adoptive transfer of xenoantigen‑stimulated T cell receptor Vβ‑restricted human regulatory T cells prevents porcine islet xenograft rejection in humanized mice.
Adoptive transfer of xenoantigen‑stimulated T cell receptor Vβ‑restricted human regulatory T cells prevents porcine islet xenograft rejection in humanized mice.
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DOI：
10.3892/mmr.2018.9471
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发表时间：
2018-11
影响因子：
3.4
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Jin X;Hu M;Gong L;Li H;Wang Y;Ji M;Li H
人调节性T细胞（TCRs）的多克隆扩增通过抑制效应T细胞应答在体外和体内防止异种排斥。然而，使用多克隆扩增的THBE的主要限制是它们可能引起泛免疫抑制作用。本研究旨在比较离体扩增的人异种抗原刺激的TCLs（Xeno-Treg）和多克隆TCLs（Poly-Treg）在NOD-SCID白细胞介素（IL）-2受体（IL 2 r）γ−/−小鼠中保护胰岛异种移植物免受排斥反应的能力。用猪外周血单个核细胞（PBMCs）或抗CD 3/CD 28微球刺激扩增人CD 4+ CD 25 + CD 127 lo T细胞，通过免疫细胞表型分析、T细胞受体（TCR）Vβ CDR 3谱分析和体外抑制活性测定，对扩增的人CD 4+ CD 25 + CD 127 lo T细胞进行鉴定。使用移植到NOD-SCID IL-2 r γ−/−小鼠中的新生猪胰岛细胞簇（NICC），在体内评价过继转移的离体人TclG的效率，所述NOD-SCID IL-2 r γ−/−小鼠接受有或没有Xeno-Treg或Poly-Treg的人PBMC。表达增加的人类白细胞抗原-DR水平和分泌更高水平的IL-10的Xeno-Treg在猪-人混合淋巴细胞反应中表现出增强的抑制能力。与Poly-Treg相比，Xeno-Treg中TCR Vβ4、Vβ10、Vβ18和Vβ20的谱图显示限制性和扩增克隆的大小分别为205、441、332和196。用人PBMC和Poly-Treg重建小鼠在第63天导致NICC异种移植排斥。人PBMC和Xeno-Treg的连续转移延长了胰岛异种移植物的存活超过84天，移植物含有完整的胰岛素分泌细胞，周围有少量的人CD 45+细胞。这项研究表明，与Poly-Treg相比，过继转移离体扩增的人Xeno-Treg可以有效预防人源化NOD-SCID IL 2 r γ−/−小鼠中的胰岛异种移植排斥反应。这些发现表明，过继性Treg治疗可通过最小化全身免疫抑制用于胰岛异种移植中的免疫调节。
Polyclonal expansion of human regulatory T cells (Tregs) prevents xenogeneic rejection by suppressing effector T cell responses in vitro and in vivo. However, a major limitation to using polyclonally expanded Tregs is that they may cause pan-immunosuppressive effects. The present study was conducted to compare the ability of ex vivo expanded human xenoantigen-stimulated Tregs (Xeno-Treg) and polyclonal Tregs (Poly-Treg) to protect islet xenografts from rejection in NOD-SCID interleukin (IL)-2 receptor (IL2r)γ−/− mice. Human cluster of differentiation (CD)4+CD25+CD127lo Tregs, expanded either by stimulating with porcine peripheral blood mononuclear cells (PBMCs) or anti-CD3/CD28 beads, were characterized by immune cell phenotyping, T cell receptor (TCR) Vβ CDR3 spectratyping and performing suppressive activity assays in vitro. The efficiency of adoptively transferred ex vivo human Tregs was evaluated in vivo using neonatal porcine islet cell clusters (NICC) transplanted into NOD-SCID IL-2rγ−/− mice, which received human PBMCs with or without Xeno-Treg or Poly-Treg. Xeno-Treg, which expressed increased levels of human leukocyte antigen-DR and secreted higher levels of IL-10, demonstrated enhanced suppressive capacity in a pig-human mixed lymphocyte reaction. Spectratypes of TCR Vβ4, Vβ10, Vβ18 and Vβ20 in Xeno-Treg showed restriction and expanded clones at sizes of 205, 441, 332 and 196 respectively, compared to those of Poly-Treg. Reconstitution of mice with human PBMCs and Poly-Treg resulted in NICC xenograft rejection at 63 days. Adoptive transfer with human PBMCs and Xeno-Treg prolonged islet xenograft survival beyond 84 days, with grafts containing intact insulin-secreting cells surrounded by a small number of human CD45+ cells. This study demonstrated that adoptive transfer of ex vivo expanded human Xeno-Treg may potently prevent islet xenograft rejection in humanized NOD-SCID IL2rγ−/− mice compared with Poly-Treg. These findings suggested that adoptive Treg therapy may be used for immunomodulation in islet xenotransplantation by minimizing systemic immunosuppression.
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影响因子：
4.6
作者：
Ma B;Yang JY;Song WJ;Ding R;Zhang ZC;Ji HC;Zhang X;Wang JL;Yang XS;Tao KS;Dou KF;Li X
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Li X
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影响因子：
4.4
作者：
Baecher-Allan, Clare;Wolf, Elizabeth;Haller, David A.
通讯作者：
Haller, David A.
影响因子：
1.5
作者：
Butler, James R.;Wang, Zheng-Yu;Tector, A. Joseph
通讯作者：
Tector, A. Joseph
影响因子：
3.9
作者：
Lee, Jae-Il;Kim, Jiyeon;Park, Seong Hoe
通讯作者：
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