Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model
Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model
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DOI：
10.1016/j.bbmt.2018.04.026
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发表时间：
2018-09-01
影响因子：
4.3
通讯作者：
Levy, Robert B.
中科院分区：
文献类型：
--
作者：
Copsel, Sabrina;Wolf, Dietlinde;Levy, Robert B.
调节性T细胞（Tcells）对于维持耐受性和免疫稳态是必不可少的。在异基因造血干细胞移植（aHSCT）中，转移适当数量的Treg是预防移植物抗宿主病（GVHD）的有前景的疗法。我们最近报道了一种新的方法，通过靶向肿瘤坏死因子受体超家族25（TNFRSF25）和CD25，诱导体内TcB的显着扩增和选择性激活。一个潜在的进步，以促进临床应用的TCLB改善GVHD和其他疾病将是产生更有效的Treg群体。在这里，我们想要确定使用"2-途径"刺激方案通过TL1A-Ig融合蛋白和低剂量IL-2（分别靶向TNFRSF25和CD25）产生的非常低剂量的TcR是否可以用于调节临床前GVHD。对这种2-途径扩增的TclB的分析鉴定出与未扩增的TclB相比更高水平的活化和功能分子（CD103、ICOS-1、Nrp-1、CD39、CD73、it-10和tgfbl）。此外，在体外评估2-途径刺激TcB表明增强的抑制活性。值得注意的是，极低数量的这些TcM（1：6扩增的TcM/常规T细胞）的移植抑制了MHC错配的aHSCT后的GVHD。总体而言，这些结果表明，2-途径刺激的CD4（+）FoxP3（+）TcB在定量和定性上比未扩增的TcB更有效。总之，本研究中的发现支持这样的观点，即这种2-通路刺激的TcR可能有助于预防GVHD，并最终促进aHSCT在临床中更广泛的应用。(C)2018年美国血液和骨髓移植协会。
Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach that induces the marked expansion and selective activation of Tregs in vivo by targeting tumor necrosis factor receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Tregs to ameliorate GVHD and other disorders would be the generation of more potent Treg populations. Here we wanted to determine if very low doses of Tregs generated using the "2-pathway" stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD. Analysis of such 2-pathway expanded Tregs identified higher levels of activation and functional molecules (CD103, ICOS-1, Nrp-1, CD39, CD73, it-10, and tgfbl) versus unexpanded Tregs. Additionally, in vitro assessment of 2-pathway stimulated Tregs indicated enhanced suppressor activity. Notably, transplant of extremely low numbers of these Tregs (1:6 expanded Tregs/conventional T cells) suppressed GVHD after an MHC-mismatched aHSCT. Overall, these results demonstrate that 2-pathway stimulated CD4(+) FoxP3(+) Tregs were quantitatively and qualitatively more functionally effective than unexpanded Tregs. In total, the findings in this study support the notion that such 2-pathway stimulated Tregs may be useful for prevention of GVHD and ultimately promote more widespread application of aHSCT in the clinic. (C) 2018 American Society for Blood and Marrow Transplantation.