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目的:探讨新型免疫抑制药物雷帕霉素(RAPA)对小鼠异基因骨髓移植(allo-BMT)后急性移植物抗宿主病(aGVHD)的抑制作用,并与传统免疫抑制药物比较作用效果。方法:用主要组织相容性抗原(MHC)完全不合的纯种近交系小鼠[供鼠为雄性C57BL/6 J(H-2b)鼠,受鼠为雌性BALB/c(H-2d)鼠]建立allo-BMT/aGVHD动物模型,随机分5组,第1、2和3组分别给予RAPA、环孢菌素A(CsA)加甲氨蝶呤(MTX)、RAPA加CsA加MTX联合用药作为aGVHD抑制方案,第4组为空白对照,第5组为未移植组。观察各组小鼠骨髓移植后aGVHD的出现情况。结果:移植小鼠出现典型的aGVHD症状,未用aGVHD预防方案的移植小鼠(第4组)死亡高峰在移植后第5~7天,死亡率达100%。用不同aGVHD预防方案的第1~3组小鼠aGVHD症状明显减轻,平均生存时间(MST)较第4组显著延长(分别延长3.5、1.9和6.0 d,P<0.05)。不同aGVHD预防方案的移植小鼠之间,移植后外周血常规变化差异无显著性。经用各预防方案后,移植小鼠aGVHD病理表现减轻,且RAPA、CsA和MTX联合用药组的病理分级轻于RAPA单药组或CsA加MTX标准方案组。结论:RAPA可以显著抑制体外T淋巴细胞增殖效应,增强小鼠对骨髓移植的免疫耐受,对小鼠骨髓移植后移植物抗宿主病(GVHD)有明显抑制作用,可减轻GVHD症状和病理损害程度,延长平均生存时间。
Objective: To investigate the inhibitory effect of a novel immunosuppressive drug rapamycin on acute graft-versus-host disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) in mice and its effect compared with conventional immunosuppressive drugs. Methods: Purebred inbred mice with male-major male C57BL / 6 J (H-2b) mice that were completely incompatible with major histocompatibility antigen (MHC) and female mice with BALB / c (H-2d) Rat] Allo-BMT / aGVHD animal model was established and randomly divided into 5 groups. Groups 1, 2 and 3 were given RAPA, cyclosporine A (CsA) plus methotrexate (MTX), RAPA plus CsA plus MTX Medication as aGVHD inhibition program, the fourth group of blank control, the fifth group of non-transplant group. The incidence of aGVHD after bone marrow transplantation in each group was observed. Results: The typical aGVHD symptoms were found in the transplanted mice. The peak of death in transplanted mice without aGVHD prophylaxis (group 4) was 100% after 5 to 7 days after transplantation. The symptoms of aGVHD in groups 1 ~ 3 with different aGVHD prophylaxis were significantly reduced, and the mean survival time (MST) was significantly longer than that in group 4 (3.5, 1.9 and 6.0 d, respectively, P <0.05). There was no significant difference in the routine changes of peripheral blood after transplantation between different aGVHD prophylaxis programs. The pathological changes of aGVHD in mice transplanted were relieved with each prophylaxis scheme. The pathological grading of RAPA, CsA and MTX combination groups was lighter than that of RAPA single group or CsA plus MTX standard regimen. Conclusion: RAPA can significantly inhibit the proliferation of T lymphocytes in vitro and enhance the tolerance of mice to bone marrow transplantation. It can significantly inhibit the graft-versus-host disease (GVHD) after bone marrow transplantation in mice and reduce the symptoms and pathological changes of GVHD Extent, extend the average survival time.