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

本研究旨在建立联合应用造血因子治疗儿童血液病/肿瘤性疾病中的血小板减少症的方法。为了获得更好的造血细胞因子治疗，首先在小鼠和人的培养系统中，用IL-3、IL-6、IL-11、G-CSF、GM-CSF、M-CSF、EPO和干细胞因子(SCF)研究了造血因子对血小板生成的协同作用。然后，对患有再生障碍性贫血或急性白血病的儿童进行了几种造血因子的联合治疗。体外造血因子的协同作用(1)IL-6和IL-11对巨核细胞集落形成的刺激作用可通过在小鼠培养体系中加入IL-3而增强。(2)在人的培养体系中，IL-6、IL-11或SCF单独对巨核细胞的生长没有刺激作用。当SCF与IL-6或IL-11联合使用时，可形成明显的巨核细胞集落。(3)SCF对原始巨核系祖细胞(巨核细胞集落刺激因子)的增殖有促进作用，但对巨核细胞的成熟无明显影响。因此，SCF在临床上应与IL-6、IL-11等巨核细胞增强剂联合应用。(4)IL-3、IL-6、IL-11、GM-CSF、M-CSF或EPO单独或联合应用可促进部分再生障碍性贫血患儿巨核细胞集落形成。造血细胞因子治疗早产儿血小板减少症(1)应用G-CSF、G-CSF+GM-CSF或G-CSF+EPO可提高部分再生障碍性贫血患者的血小板数。(2)EPO对早产儿贫血的促血小板作用得到证实。

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.