Lim Jung-Yeon, Im Keon-Il, Song Yunejin, Kim Nayoun, Nam Young-Sun, Jeon Young-Woo, Cho Seok-Goo
Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, Seoul, Korea.
Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Korean J Intern Med. 2018 Sep;33(5):980-989. doi: 10.3904/kjim.2016.319. Epub 2017 Oct 19.
BACKGROUND/AIMS: Adoptive therapy with regulatory T (Treg) cells to prevent graft-versus-host disease (GVHD) would benefit from a strategy to improve homing to the sites of inflammation following hematopoietic stem cell transplantation (HSCT). Although donor-derived Treg cells have mainly been used in these models, third-party-derived Treg cells are a promising alternative for cell-based immunotherapy, as they can be screened for pathogens and cell activity, and banked for GVHD prevention. In this study, we explored major histocompatibility complex (MHC) disparities between Treg cells and conventional T cells in HSCT to evaluate the impact of these different cell populations on the prevention of acute GVHD, as well as survival after allogeneic transplantation.
To induce acute GVHD, lethally irradiated BALB/c (H-2d) mice were transplanted with 5 × 105 T cell-depleted bone marrow cells and 5 × 105 CD4+CD25- splenic T cells from C57BL/6 (H-2b) mice. Recipients were injected with 5 × 105 cultured donor-, host-, or third-party-derived CD4+CD25+CD62L+ Treg cells (bone marrow transplantation + day 1).
Systemic infusion of three groups of Treg cell improved clinicopathological manifestations and survival in an acute GVHD model. Although donor-derived Treg cells were immunologically the most effective, the third-party-derived Treg cell therapy group displayed equal regulation of expansion of CD4+CD25+- Foxp3+ Treg cells and suppressive CD4+IL-17+ T-helper (Th17) cells in ex vivo assays compared with the donor- and host-derived groups.
Our findings demonstrate that the use of third-party Treg cells is a viable alternative to donor-derived Treg cellular therapy in clinical settings, in which human leukocyte antigen-matched donors are not always readily available.
背景/目的：采用调节性T（Treg）细胞进行过继性治疗以预防移植物抗宿主病（GVHD），若能改善造血干细胞移植（HSCT）后炎症部位的归巢策略则将从中受益。尽管在这些模型中主要使用供体来源的Treg细胞，但第三方来源的Treg细胞是基于细胞的免疫治疗的一个有前景的替代方案，因为它们可以进行病原体和细胞活性筛查，并储存用于预防GVHD。在本研究中，我们探讨了HSCT中Treg细胞与常规T细胞之间的主要组织相容性复合体（MHC）差异，以评估这些不同细胞群体对预防急性GVHD以及异基因移植后生存的影响。
为诱导急性GVHD，对经致死剂量照射的BALB/c（H-2d）小鼠移植5×105个去除T细胞的骨髓细胞和来自C57BL/6（H-2b）小鼠的5×105个CD4+CD25-脾T细胞。受体在骨髓移植+第1天注射5×105个培养的供体、宿主或第三方来源的CD4+CD25+CD62L+Treg细胞。
在急性GVHD模型中，全身输注三组Treg细胞均改善了临床病理表现并提高了生存率。尽管供体来源的Treg细胞在免疫方面最有效，但与供体和宿主来源的组相比，第三方来源的Treg细胞治疗组在体外试验中对CD4+CD25+-Foxp3+Treg细胞和抑制性CD4+IL-17+辅助性T（Th17）细胞的扩增具有同等的调节作用。
我们的研究结果表明，在临床环境中，当人类白细胞抗原匹配的供体并非总是容易获得时，使用第三方Treg细胞是供体来源的Treg细胞治疗的可行替代方案。
