Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.
Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.
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DOI：
10.1016/j.jcyt.2013.07.009
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发表时间：
2014-01
期刊：
影响因子：
4.5
通讯作者：
Shpall EJ
中科院分区：
文献类型：
--
作者：
Parmar S;Liu X;Tung SS;Robinson SN;Rodriguez G;Cooper LJ;Yang H;Shah N;Yang H;Konopleva M;Molldrem JJ;Garcia-Manero G;Najjar A;Yvon E;McNiece I;Rezvani K;Savoldo B;Bollard CM;Shpall EJ
自然发生的调节性T细胞（Treg）正在成为预防移植物抗宿主病（GvHD）的一种有希望的方法，GvHD仍然是同种异体造血干细胞移植成功结果的障碍。然而，Treg仅占脐带血（CB）中有核细胞总数的1-5% （<3×106细胞），因此需要新的Treg扩增方法来产生与临床相关的数量。目前有几种方法被用于体外Treg扩展。在这里，我们报道了一种从CB中扩增Treg的新方法，并在体外通过减弱异体混合淋巴细胞反应证明了它们的有效性，在体内通过使用异种GvHD小鼠模型来预防GvHD。利用磁细胞分选，通过CD25+细胞的阳性选择，从CB中分离出天然存在的Treg。使用CD3/28共表达dynabead和白细胞介素(IL)-2将这些扩展到临床相关数量。体外扩增Treg为CD4+25+FOXP3+127lo，表达多克隆t细胞受体Vβ库。与常规t淋巴细胞（CD4+25-细胞）相比，Treg在体外一致表现出FOXP3 TSDR启动子区域的去甲基化和异体增殖反应的抑制。在我们的NOD-SCID il - 2r - γ缺失（NSG）异种GvHD模型中，预防性注射第三方cb衍生的体外扩增Treg可预防GvHD，从而改善GvHD评分，降低循环炎症因子，显著提高总生存期。该异种GvHD模型可用于研究CB Treg的作用机制以及其他治疗干预措施。
Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host Disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3×106 cells) and therefore novel methods of Treg expansion to generate clinically-relevant numbers are needed. Several methodologies are currently being utilized for ex vivo Treg expansion. Here, we report a new approach to expand Treg from CB and demonstrate their efficacy in vitro by blunting allogeneic mixed lymphocyte reactions and in vivo by preventing GvHD using a xenogenic GvHD mouse model. Using magnetic cell sorting, naturally-occurring Treg were isolated from CB by the positive selection of CD25+ cells. These were expanded to clinically-relevant numbers using CD3/28 co-expressing Dynabeads and interleukin (IL)-2. Ex vivo-expanded Treg were CD4+25+FOXP3+127lo and expressed a polyclonal T-cell receptor Vβ repertoire. When compared to conventional T-lymphocytes (CD4+25- cells), Treg consistently showed demethylation of the FOXP3 TSDR promoter region and suppression of allogeneic proliferation responses in vitro. In our NOD-SCID IL-2Rγnull (NSG) xenogeneic model of GvHD, prophylactic injection of 3rd party CB-derived, ex vivo-expanded Treg led to the prevention of GvHD that translated into improved GvHD score, decreased circulating inflammatory cytokines and significantly superior overall survival. This model of xenogenic GvHD can be used to study the mechanism of action of CB Treg as well as other therapeutic interventions.
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影响因子：
56.9
作者：
Arstila, TP;Casrouge, A;Kourilsky, P
通讯作者：
Kourilsky, P
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.3
作者：
Cao, Tinghua;Soto, Allis;Li, Li
通讯作者：
Li, Li
影响因子：
20.3
作者：
Taylor, PA;Lees, CJ;Blazar, BR
通讯作者：
Blazar, BR
影响因子：
20.3
作者：
Godfrey, WR;Spoden, DJ;Porter, SB
通讯作者：
Porter, SB