Bone Marrow Transplant Team, Mater Medical Research Institute, South Brisbane QLD 4101 Australia.
Haematologica. 2010 Dec;95(12):2102-10. doi: 10.3324/haematol.2010.028910. Epub 2010 Aug 26.
BACKGROUND: Multipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo. DESIGN AND METHODS: We examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major histocompatibility complex-mismatched: UBI-GFP/BL6 [H-2(b)]→BALB/c [H-2(d)] and the sibling transplant mimic, UBI-GFP/BL6 [H-2(b)]→BALB.B [H-2(b)]) using clinically relevant conditioning regimens. We also examined the effect of mesenchymal stromal cell infusion on bone marrow and spleen cellular composition and cytokine secretion in transplant recipients. RESULTS: Despite T-cell suppression in vitro, mesenchymal stromal cells delayed but did not prevent graft-versus-host disease in the major histocompatibility complex-mismatched model. In the sibling transplant model, however, 30% of mesenchymal stromal cell-treated mice did not develop graft-versus-host disease. The timing of administration and dose of the mesenchymal stromal cells influenced their effectiveness in attenuating graft-versus-host disease, such that a low dose of mesenchymal stromal cells administered early was more effective than a high dose of mesenchymal stromal cells given late. Compared to control-treated mice, mesenchymal stromal cell-treated mice had significant reductions in serum and splenic interferon-γ, an important mediator of graft-versus-host disease. CONCLUSIONS: Mesenchymal stromal cells appear to delay death from graft-versus-host disease by transiently altering the inflammatory milieu and reducing levels of interferon-γ. Our data suggest that both the timing of infusion and the dose of mesenchymal stromal cells likely influence these cells' effectiveness in attenuating graft-versus-host disease.
背景：多能间充质基质细胞在体外抑制 T 细胞功能，这一特性使其在异基因造血干细胞移植后治疗临床类固醇难治性移植物抗宿主病中得到应用。然而，间充质基质细胞解决移植物抗宿主病的潜力受到缺乏体内免疫调节作用的临床前数据的影响。
设计和方法：我们使用临床相关的预处理方案，在两种移植物抗宿主病模型（主要组织相容性复合物不匹配：UBI-GFP/BL6[H-2(b)]→BALB/c[H-2(d)]和同胞移植模拟物，UBI-GFP/BL6[H-2(b)]→BALB.B[H-2(b)])中检查供体来源的间充质基质细胞的时间和剂量对移植物抗宿主病动力学的影响。我们还检查了间充质基质细胞输注对移植受者骨髓和脾脏细胞组成和细胞因子分泌的影响。
结果：尽管体外 T 细胞抑制作用，间充质基质细胞延迟但不能预防主要组织相容性复合物不匹配模型中的移植物抗宿主病。然而，在同胞移植模型中，30%的间充质基质细胞治疗小鼠未发生移植物抗宿主病。间充质基质细胞的给药时间和剂量影响其减轻移植物抗宿主病的效果，例如，早期给予低剂量的间充质基质细胞比晚期给予高剂量的间充质基质细胞更有效。与对照治疗的小鼠相比，间充质基质细胞治疗的小鼠血清和脾脏中干扰素-γ显著减少，干扰素-γ是移植物抗宿主病的重要介质。
结论：间充质基质细胞通过暂时改变炎症环境和降低干扰素-γ水平，似乎延迟了移植物抗宿主病的死亡。我们的数据表明，间充质基质细胞输注的时间和剂量都可能影响这些细胞减轻移植物抗宿主病的效果。
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