TJU103对小鼠同种异基因造血干细胞移植模型GVHD的预防作用

目的探讨TJU103对小鼠同种异基因造血干细胞移植模型移植物抗宿主病(GVHD)是否起预防作用。方法(1)用单向混合淋巴细胞培养方法检测TJU103对T淋巴细胞增殖的影响;(2)以BALB/c(H-2d)、CB6F1(H-2d/b)分别作为完全异基因移植和半相合基因移植的受鼠,给予9.0Gy全身照射后4h,单纯照射组经尾静脉注射0.3mlD-Hank's液,不进行细胞移植;对照组经尾静脉注射C57BL/6小鼠混合细胞悬液(4.5×106骨髓细胞 3.0×107脾细胞),但不进行其他治疗处理;实验组经尾静脉注射C57BL/6小鼠混合细胞悬液(4.5×106骨髓细胞 3.0×107脾细胞) TJU103(终浓度25μg/ml),此后腹腔注射TJU10350μg/d,共7d,然后观察其造血恢复、植入及GVHD的情况。结果(1)TJU103可以显著抑制T细胞活化增殖,其抑制作用呈剂量依赖性,在25μg/ml浓度时,可以抑制83%细胞增殖。(2)由于没有给予GVHD防治措施,对照组受鼠GVHD的发生率和死亡率分别为10/10和10/10;而完全异基因移植实验组小鼠GVHD发生率仅为2/10,30d生存率增加至8/10(P<0.01),中位生存期延长至30d以上(P<0.01);半相合基因移植实验组小鼠GVHD发生率为1/10,30d生存率增加至9/10(P<0.01),中位生存期延长至30d以上(P<0.01)。结论TJU103不仅可以显著抑制体外T淋巴细胞增殖效应,而且可显著降低小鼠同种异基因造血干细胞移植模型GVHD的发生率。

Role of T JU103 in prevention of graft-versus-host disease after allogeneic stem cell transplantation in mice

OBJECTIVE: To explore the role of TJU103 in preventing graft-versus-host disease (GVHD) after allogeneic stem cell transplantation in mice. METHODS: BALB/c mouse splenic lymphocytes were collected and treated by mitomycin as the activating cells and the C57BL/6 mouse splenic lymphocytes as the reacting cells. In the experimental groups, the effect of TJU103 on the proliferative response of T cells was observed. BALB/c(H-2d) and CB6F1(H-2d/b) mice were used as the MHC-full-mismatched recipients and MHC-haplo-identical recipients, respectively, and pretreated by total body irradiation at 9.0 Gy before transplantation. For the recipients of the irradiation group, 0.3 ml D-Hank's solution was injected through the tail vein without cell transplantation, the recipients of the control group received injection of 4.5x10(6) bone marrow cells mixed with 3.0x10(7) spleen cells from C57BL/6 mice through the tail vein, and those in the experimental group received cell transplantation in the same manner with also injection via the tail vein of 25 microg/ml TJU103, which was subsequently injected intraperitoneally for 7 consecutive days at daily dose of 50 microg. The hematopoietic recovery, engraftment and GVHD of the recipients were observed. RESULTS: TJU103 resulted in a dose-dependent inhibition of T cell proliferation in mixed lymphocyte reaction (MLR), and nearly 83% inhibition of the proliferative response was observed with the addition of 25 microg/ml of TJU103. Without any treatment, the occurrence of GVHD and death rate in the control group was both 10/10. Daily injection of TJU103 at 50 microg for the initial post-transplantation week protected the mice from GVHD. In the MHC-full-mismatched model, the incidence of GVHD and survival rate on day 30 of the experiment group was 2/10 and 8/10, showing significant difference from those in the control group (P<0.01). The median survival time (MST) was 30 days in the experimental group versus 15 days in the control group (P<0.05). In the MHC-haplo-identical model, the incidence of GVHD and the survival rate on day 30 of the experimental group was 1/10 and 9/10, which were significantly different from the control group (P<0.01). The MST was 30 days in the experimental group versus 14 days in the control group (P<0.05). CONCLUSION: TJU103 is capable of markedly inhibiting T cell proliferative response in vitro and can decrease GVHD incidence after allogeneic stem cell transplantation in mice.