Establishment of hemopoietic cytokine therapy with a combination of hemopoietic factors for thrombocytopenia of childhood

本研究旨在建立造血细胞因子联合造血因子治疗儿童血液学/肿瘤疾病中血小板减少症的方法。为了更好地发挥造血细胞因子的作用，我们首先利用IL-3、IL-6、IL-11、G-CSF、GM-CSF、M-CSF、促红细胞生成素（EPO）和干细胞因子（SCF）在小鼠和人培养系统中研究了造血因子对血小板生成的协同作用。然后，对再生障碍性贫血或急性白血病的儿童使用几种造血因子组合。体外造血因子的协同作用(1)在小鼠培养系统中，IL-3的加入增强了IL-6和IL-11对巨核细胞集落形成的刺激作用。(2)在人培养体系中，单独使用IL-6、IL-11或SCF对巨核细胞的生长没有刺激作用。当SCF与IL-6或IL-11结合时，巨核细胞集落明显形成。这些结果在CD34+细胞的实验中得到了证实。(3) SCF对原始巨核细胞祖细胞（巨核细胞集落刺激因子）的增殖有刺激作用，但对巨核细胞的成熟没有刺激作用（巨核细胞增强因子）。因此，SCF在临床应用时应与巨核细胞增强剂如IL-6和IL-11联合使用。(4) IL-3、IL-6、IL-11、GM-CSF、M-CSF或EPO单独或联合使用可增加部分再生障碍性贫血患儿巨核细胞集落形成。造血细胞因子治疗血小板减少症(1)G-CSF、G-CSF + GM-CSF或G-CSF + EPO可使部分再生障碍性贫血患者的血小板数量增加。(2)在EPO治疗早产儿贫血中证实了EPO增加血小板计数的作用。

The present studies were conducted to establish hemopoietic cytokine therapy with a combination of hemopoietic factors for thrombocytopenia in several hematologic/neoplastic disorders of childhood. To make the better hemopoietic cytokine therapy, synergic effects of hemopoietic factors on the thrombopoiesis were first studied in the mouse and human culture systems using IL-3, IL-6, IL-11, G-CSF, GM-CSF, M-CSF, erythropoietin (EPO) and stem cell factor (SCF). Then, several combinations of hemopoietic factors were administered in children with aplastic anemia or acute leukemia.1. Synergic effects of hemopoietic factors in vitro(1) The stimulatory effects of IL-6 and IL-11 on the megakaryocyte colony formation were augmented by the addition of IL-3 in the mouse culture system.(2) In the human culture system, IL-6, IL-11 or SCF alone did not have the stimulatory effects on the megakaryocyte growth. When SCF was combined with IL-6 or IL-11, there was significant formation of megakaryocyte colonies. These results were confirmed in the experiments using CD34+ cells.(3) SCF had stimulatory effects on the proliferation of primitive megakaryocytic progenitors (megakaryocyte colony-stimulating factor) but not on the maturation of megakaryocytes (megakaryocyte potentiator). Thus, SCF should be administered in the clinical use in combination with such megakaryocyte potentiators as IL-6 and IL-11.(4) IL-3, IL-6, IL-11, GM-CSF, M-CSF or EPO alone or in combination could increase the megakaryocyte colony formation in some children with aplastic anemia.2. Hemopoietic cytokine therapy for thrombocytopenia(1) The administration of G-CSF, G-CSF + GM-CSF or G-CSF + EPO increased the number of platelets in some patients with aplastic anemia.(2) The effect of EPO to increase platelet counts was confirmed in the EPO therapy for anemia of prematurity.