Activation of natural killer T cells enhances the function of regulatory T-cell therapy in suppressing murine GVHD
Activation of natural killer T cells enhances the function of regulatory T-cell therapy in suppressing murine GVHD
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DOI：
10.1182/bloodadvances.2020003272
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发表时间：
2021-06-08
期刊：
影响因子：
7.5
通讯作者：
Negrin, Robert S.
中科院分区：
文献类型：
--
作者：
Hirai, Toshihito;Lin, Po-Yu;Negrin, Robert S.
在动物模型和1/2期临床试验中，使用调节性T细胞（TCFs）的细胞疗法已显示出抑制移植物抗宿主病（GVHD）同时保持移植物抗肿瘤效应的有希望的结果。然而，外周血中缺乏TCFs使得难以获得足够数量的细胞，并阻碍了进一步的临床应用。不变的自然杀伤T（iNKT）细胞构成调节细胞的另一个区室，其通过在其自身用α-半乳糖神经酰胺（α-GalCer）激活或过继转移后激活TcR来改善GVHD。我们在此证明，α-GalCer脂质体（α-GalCer-lipo）的单次施用增强了在鼠GVHD模型中过继转移后Treg的体内扩增，并且甚至在注射其它次优细胞数后也改善了Treg疗法的治疗功效。GVHD抑制需要宿主iNKT细胞而不是供体iNKT细胞，因为在将来自野生型（WT）C57 BL/6小鼠的细胞移植到J α 18（-/-）iNKT细胞缺陷型BALB/c小鼠中时未显示出α-GalCer-脂体施用的存活益处，而从J α 18（-/-）C57 BL/6供体小鼠移植到WT BALB/c受体小鼠中时观察到了这一益处。iNKT细胞活化和Treg过继疗法的组合可通过增强功效和减少所需的Treg数量而使Treg疗法更可行和更安全。
Cellular therapy with regulatory T cells (Tregs) has shown promising results for suppressing graft-versus-host disease (GVHD) while preserving graft vs tumor effects in animal models and phase 1/2 clinical trials. However, a paucity of Tregs in the peripheral blood makes it difficult to acquire sufficient numbers of cells and hampers further clinical application. Invariant natural killer T (iNKT) cells constitute another compartment of regulatory cells that ameliorate GVHD through activation of Tregs after their own activation with a-galactosylceramide (a-GalCer) or adoptive transfer. We demonstrate here that a single administration of a-GalCer liposome (a-GalCer-lipo) enhanced the in vivo expansion of Tregs after adoptive transfer in a murine GVHD model and improved therapeutic efficacy of Treg therapy even after injection of otherwise suboptimal cell numbers. Host iNKT cells rather than donor iNKT cells were required for GVHD suppression because the survival benefit of a-GalCer-lipo administration was not shown in the transplantation of cells from wild-type (WT) C57BL/6 mice into J alpha 18(-/-) iNKT cell-deficient BALB/c mice, whereas it was observed from J alpha 18(-/-) C57BL/6 donor mice into WT BALB/c recipient mice. The combination of iNKT cell activation and Treg adoptive therapy may make Treg therapy more feasible and safer by enhancing the efficacy and reducing the number of Tregs required.