细胞因子联合应用对重度骨髓型急性放射病猴的治疗作用研究

Therapeutic Effect of Combined Cytokines on Nonhuman Primate Model of Severe Haemopoietic Acute Radiation Sickness

目的:观察重组人粒细胞集落刺激因子(rh G-CSF)、重组人血小板生成素(rh TPO)与重组人白介素2(rh IL-2)联合应用对重度骨髓型急性放射病(ARS)恒河猴的治疗作用。方法:给予17只恒河猴7.0 Gy^(60)Coγ射线全身照射,以建立重度骨髓型ARS模型,并将其随机分为对症治疗、rh G-CSF+rh TPO和rh G-CSF+rh TPO+rh IL-2治疗3组。之后观察各组动物存活时间、出血、感染等一般体征及外周血象变化,骨髓集落形成能力和照射后45 d骨髓的病理组织学变化。结果:7.0 Gy^(60)Coγ射线照射后,对症治疗组动物出现柏油便和呕吐症状,该组5只动物于照射后12-18 d死亡,整体存活率为16.7%;细胞因子组胃肠道反应不明显,动物100%存活。照射后各组动物外周血各类细胞数急剧下降,两种细胞因子联合治疗方案均可明显提高各系血细胞最低值,并缩短低值持续时间,恢复时间提前;与rh G-CSF+rh TPO治疗相比,rh G-CSF+rh TPO+rh IL-2治疗可明显提高单核细胞和淋巴细胞数。照射后2 d骨髓中造血干/祖细胞集落形成率明显下降,照射后29 d细胞因子治疗能明显促进集落形成能力;对症治疗组动物骨髓造血细胞大部分消失,细胞因子治疗能明显促进骨髓造血功能恢复。结论:rh G-CSF+rh TPO与rh G-CSF+rh TPO+rh IL-2两种细胞因子组合均可显著促进7.0 Gy^(60)Coγ射线照射的恒河猴造血功能恢复,提高重度骨髓型ARS猴的存活率;rh IL-2可以明显加快外周血中白细胞特别是淋巴细胞和单核细胞的恢复。在积极对症治疗的基础上采用rh G-CSF、rh TPO与rh IL-2的联合序贯治疗是治疗重度骨髓型ARS的有效方法。

Objective:To evaluate the therapeutic effects of combined administration of recombinant human granulocyte colony-stimulating factor（rhG-CSF）,recombinant human thrombopoietin（rhTPO） and recombinant human interleukin-2（rhIL-2） on radiation-induced severe haemopoietic acute radiation sickness（ARS） in rhesus monkeys,so as to provide experimental evidences for the effective clinical treatment.Methods:Seventeen rhesus monkeys were exposed to7.0 Gy60Co γ-ray total body irradiation（TBI） to establish severe haemopoietic ARS model,and were randomly divided into supportive care group,rhG-CSF + rhTPO treatment group and rhG-CSF + rhTPO +rhIL-2 treatment group.Survival time,general signs such as bleeding and infections,and peripheral blood cell counts in each group were monitored.Bone marrow cells were cultivated to examine the colony formation ability.The histomorphology changes of bone marrow were observed at 45 d post irradiation.Results:After 7.0 Gy 60Co γ-ray TBI,monkeys of supportive care group underwent tarry stool and emesis,then died in 12 18 d.The overall survival rate in this group was 16.7%.Gastrointestinal reactions of monkeys in two combined-cytokines treatment groups were inapparent.Combined-cytokines treatment induced 100%survival.Complete blood cells declined sharply after irradiation in each group,but two combined-cytokines treatment schemes could elevate the nadir of all blood cells,shorten the duration of pancytopenia and accelerate the recovery of hemogram.Compared with rhG-CSF + rhTPO treatment,rhG-CSF + rhTPO + rhIL-2 treatment could increase the counts of lymphocytes and monocytes.The colony-formation rate of haemopoietic stem/progenitor cells in bone marrow dropped markedly at 2 d after irradiation.Combined-cytokines treatment promoted the ability of colony formation on day 29.Hematopoietic cells mostly disappeared in bone marrow of animals in supportive care group,but hematopoietic functions were recovered after cytokines were administrated.Conclusion:rhG-CSF + rhTPO and rhGCSF + rhTPO + rhIL-2 treatment can significantly promote hematopoiesis recovery,improve the quantity of life,simplify the supportive therapy,and enhance the survival rate of rhesus monkeys with severe haemopoietic ARS induced by 7.0 Gy 60Co γ-ray exposure.Especially the application of rhIL-2 can accelerate the recovery of lymphocytes and monocytes and restore the immunological function.Thus,combination of rhG-CSF,rhTPO and rhIL-2 on the basis of supportive care is an efficient strategy to treat severe haemopoietic ARS.