Calkoen Friso G J, Vervat Carly, van Halteren Astrid G S, Welters Marij J P, Veltrop-Duits Louise A, Lankester Arjan C, Egeler R Maarten, Ball Lynne M, van Tol Maarten J D
Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Stem Cells Transl Med. 2014 Aug;3(8):899-910. doi: 10.5966/sctm.2013-0191. Epub 2014 Jun 5.
Beneficial effects of mesenchymal stromal cells (MSCs) in patients with severe steroid-refractory acute graft-versus-host disease (aGvHD) have been reported. However, controversy exists about the effect of MSCs on virus-specific T cells. We evaluated 56 patients with grade II-IV aGvHD who responded to steroids (n = 21) or were steroid refractory receiving either MSCs (n = 22) or other second-line therapy (n = 13). Although the overall incidence of cytomegalovirus (CMV), Epstein-Barr virus, and human adenovirus (HAdV) infections was not significantly increased, HAdV infection was associated with decreased survival in children treated with MSCs. Thus, we investigated in vitro the effects of MSCs on virus-specific T cells. Both CMV-specific and, to a lesser extent, HAdV-specific T-cell activation and proliferation were negatively affected by MSCs either after induction of a response in peripheral blood mononuclear cells (PBMCs) or after restimulation of virus-specific T-cell lines. In patient-derived PBMCs, CMV-specific proliferative responses were greatly decreased on first-line treatment of aGvHD with systemic steroids and slowly recovered after MSC administration and tapering of steroids. HAdV-specific T-cell proliferation could not be detected. In contrast, the proportion of CMV- and HAdV-specific effector T cells, measured as interferon-γ-secreting cells, remained stable or increased after treatment with MSCs. In conclusion, although in vitro experimental conditions indicated a negative impact of MSCs on CMV- and HAdV-specific T-cell responses, no solid evidence was obtained to support such an effect of MSCs on T-cell responses in vivo. Still, the susceptibility of steroid-refractory severe aGvHD patients to viral reactivation warrants critical viral monitoring during randomized controlled trials on second-line treatment including MSCs.
已有报道称间充质基质细胞（MSCs）对严重类固醇难治性急性移植物抗宿主病（aGvHD）患者具有有益作用。然而，关于MSCs对病毒特异性T细胞的影响仍存在争议。我们评估了56例II-IV级aGvHD患者，其中对类固醇有反应的患者（n = 21），或接受MSCs治疗（n = 22）或其他二线治疗（n = 13）的类固醇难治性患者。尽管巨细胞病毒（CMV）、EB病毒和人腺病毒（HAdV）感染的总体发生率没有显著增加，但HAdV感染与接受MSCs治疗的儿童生存率降低有关。因此，我们在体外研究了MSCs对病毒特异性T细胞的影响。无论是在外周血单核细胞（PBMCs）诱导反应后，还是在病毒特异性T细胞系再次刺激后，MSCs均对CMV特异性以及程度较轻的HAdV特异性T细胞活化和增殖产生负面影响。在患者来源的PBMCs中，aGvHD一线全身类固醇治疗时CMV特异性增殖反应大幅降低，在给予MSCs和逐渐减少类固醇剂量后缓慢恢复。未检测到HAdV特异性T细胞增殖。相比之下，以分泌干扰素-γ的细胞来衡量，CMV和HAdV特异性效应T细胞的比例在MSCs治疗后保持稳定或增加。总之，尽管体外实验条件表明MSCs对CMV和HAdV特异性T细胞反应有负面影响，但没有确凿证据支持MSCs在体内对T细胞反应有这种作用。尽管如此，类固醇难治性严重aGvHD患者对病毒再激活的易感性，使得在包括MSCs的二线治疗随机对照试验期间进行严格的病毒监测成为必要。
