Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation.
Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation.
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通过白细胞介素 2 和 TL1A-Ig 刺激进行的体内供体调节性 T 细胞扩增可改善移植物抗宿主病，但在造血干细胞移植后保留受者的移植物抗白血病。
DOI：
10.1016/j.bbmt.2017.02.013
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Levy,RobertB
中科院分区：
文献类型：
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作者：
Wolf,Dietlinde;Barreras,Henry;Bader,CameronS;Copsel,Sabrina;Lightbourn,CaseyO;Pfeiffer,BrentJ;Altman,NormanH;Podack,EckhardR;Komanduri,KrishnaV;Levy,RobertB
调节性T细胞（Tcells）对自身耐受性至关重要。虽然扩增的TcR的过继转移限制了造血细胞移植（HCT）后的移植物抗宿主病（GVHD），但离体产生大量功能性TcR仍然困难。在这里，我们证明了使用TL 1A-Ig融合蛋白与IL-2一起沿着体内靶向TNF超家族受体TNFRSF 25，导致供体小鼠中短暂但大量的Treg扩增，其在几天内达到峰值并且无毒。在包括血液、淋巴结、脾和结肠（GVHD靶组织）在内的多个隔室中，TcR增加。骨髓是移植物抗恶性肿瘤（GVM）反应的关键部位，TGFAP在骨髓中未扩增。在MHC不匹配或MHC匹配的allo-HSCT的情况下，体内扩增的THBE的连续转移显著改善了GVHD。关键的是，Treg扩增的供体细胞的移植促进了移植耐受，而没有GVHD，完全避免了GVM。这种方法可能被证明是一种有价值的治疗策略，促进移植耐受。
Regulatory T cells (Tregs) are critical for self-tolerance. While adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen and colon (a GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy (GVM) responses. Adoptive transfer of in vivo expanded Tregs in the setting of MHC-mismatched or MHC-matched allo-HSCT significantly ameliorated GVHD. Critically, transplant of Treg expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of GVM. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.