【摘要】 目的在骨髓移植的嵌合体中,研究供者骨髓来源的T淋巴细胞对移植物抗宿主性疾病(graft-vs.-host disease,GVHD)是否具有保护作用。方法采用T细胞去除(T cell-depleted,TCD)的Balb/c小鼠与野生型(wild type,WT)B6或TCD B6小鼠的混合骨髓细胞,输入致死量照射(8 Gy)的Balb/c小鼠体内,建立TCD Balb/c+WT B6及TCD Balb/c+TCD B6的混合嵌合体(mixed chimeras,MCs)小鼠模型。8周后,输入WT B6或SJL B6小鼠的脾细胞作为供者淋巴细胞输入(donor lymphocyte infusion,DLI)。通过比较死亡率、体质量变化、GVHD靶器官的病理损害,明确供者骨髓来源的T细胞是否减轻了DLI诱导的GVHD作用。并通过比较骨髓来源的T细胞或DLI来源的T细胞在外周血中的比例,明确骨髓来源的T细胞是否抑制了具有同种异基因反应的DLI来源的T细胞,进一步建立TCD Balb/c+CD4去除的B6或TCD Balb/c+CD8去除的B6的混合嵌合体,分别比较CD4 T或CD8 T细胞对GVHD的抑制作用。结果在含有骨髓来源的T细胞的WT嵌合体中,小鼠的生存率明显高于TCD嵌合体,而DLI后的体质量改变以及GVHD靶器官的损害程度明显轻于TCD嵌合体。而且,骨髓来源的T细胞,可抑制具有同种异基因反应的DLI来源的T细胞。同时,供者骨髓来源的CD4 T或CD8 T细胞对GVHD都起到保护作用,尤其是CD8 T细胞的保护作用更为明显。结论在DLI诱发的GVHD的混合嵌合体中,供者骨髓来源的T细胞,尤其是CD8 T细胞,有效的保护了GVHD的发生。更多还原

【Abstract】 This study designed to evaluate the protect effects of donor BM-derived T cells against GVHD in established mixed chimeras(MCs). Firstly, MCs were prepared by injecting a mixture of bone marrow cells from T cell-depleted(TCD) syngeneic Balb/c and allogeneic WT or TCD B6 into lethally irradiated(8 Gy) Balb/c mice. In MCs of TCD Balb/c+WT B6 or TCD Balb/c+TCD B6, donor lymphocyte infusion(DLI) was performed using spleen cells from WT B6 or SJL B6 donors 8 weeks after initial TCD BMC injection. Thus, survival rate, body weight change, and GVHD pathology of lung were compared to identify if BM-derived T cells can alleviate GVHD induced by DLI. The proportion of BM-derived T cells or DLI-derived T cells was detected by flow cytometry to research if BM-derived T cells can inhibit allo-reactive DLI-derived T cells. Furthermore, MCs of TCD Balb/c+CD4 depleted B6 or TCD Balb/c+CD4 depleted B6 were established to compare the inhibitory effects of CD4 and CD8 T cells against GVHD. The results showed that survival rate was significantly higher in established MCs containing BMderived T cells when compared to MCs with TCD B6; the lack of donor BM-derived T cells was markedly associated with body weight change and accumulation increase of DLI-derived allo-reactive T cells in parenchymal GVHD target tissues. Moreover, BM-derived T cells could inhibit allo-reactive DLI-derived T cells. From above,we concluded although both CD4 and CD8 T cells contributed to the protection, the latter were significantly more effective. These data represents BM-derived T cells, especially CD8 T cells, offer a potential therapeutic target for preventing and ameliorating GVHD in the setting of DLI in established mixed chimeras.更多还原