Aglietta M, Sanavio F, Stacchini A, Morelli S, Fubini L, Severino A, Pasquino P, Volta C, Bretti S, Tafuto S
Dipartimento di Scienze Biomediche ed Oncologia Umana, Università di Torino, Italy.
Blood. 1993 Oct 1;82(7):2054-61.
Human recombinant interleukin-3 (IL-3; Sandoz AG, Basel, Switzerland) was administered for 7 days to patients with neoplastic disease and normal hematopoiesis. The purpose of the study was to assess IL-3 toxicity, to identify target cells, to define their kinetics of response at different dose levels, and to determine if IL-3 in vivo increased the sensitivity of bone marrow (BM) progenitors to the action of other hematopoietic growth factors. A total of 21 patients entered the study; the dosage ranged from 0.25 to 10 micrograms/kg/d. The effect on peripheral blood cells during treatment showed no significant changes in the number of platelets, erythrocytes, neutrophils, or lymphocytes (and their subsets). A mild monocytosis and basophilia occurred. Eosinopenia, present in the first hours of treatment, was followed by a dose-and time-dependent eosinophilia. IL-3 treatment affected BM cell proliferation by increasing the percentage of BM progenitors engaged in the S-phase of the cell cycle. The effect was dose dependent, with the various progenitors showing different degrees of sensitivity. The most sensitive progenitors were the megakaryocyte progenitors (colony-forming unit-megakaryocyte), then the erythroid progenitors (burst-forming unit-erythroid), and finally the granulo-monocyte progenitors (colony-forming unit-granulocyte-macrophage) whose proliferative activity was stimulated at the higher doses of IL-3. Only a slight increase in the proliferative activity of myeloblasts, promyelocytes, and myelocytes was observed, whereas the activity of erythroblasts was unchanged. The priming effect was such that BM progenitors, purified from patients treated with IL-3, produced more colonies in vitro in the presence of granulocyte colony-stimulating factor (G-CSF; granulocyte colonies), IL-5 (eosinophil colonies), and granulocyte-macrophage CSF (GM-CSF; predominantly eosinophil colonies). These data indicate that even in vivo IL-3 acts essentially as a primer for the action of other cytokines. Therefore, optimum stimulus of myelopoiesis will require either endogenous or exogenous late-acting cytokines such as G-CSF, erythropoietin, GM-CSF, and IL-6 for achieving fully mature cells in peripheral blood. If exogenous cytokines are used with IL-3, it is likely that G-CSF will yield more neutrophils, whereas GM-CSF may enhance eosinophils, monocytes, and neutrophils. Attention to the clinical relevance of each cell type will be necessary and should determine the selection of the combination of cytokines.
将重组人白细胞介素-3（IL-3；瑞士巴塞尔山德士公司）给予患有肿瘤性疾病且造血功能正常的患者，持续用药7天。本研究的目的是评估IL-3的毒性，识别靶细胞，确定其在不同剂量水平下的反应动力学，并确定体内IL-3是否会增加骨髓（BM）祖细胞对其他造血生长因子作用的敏感性。共有21名患者进入该研究；剂量范围为0.25至10微克/千克/天。治疗期间对外周血细胞的影响显示，血小板、红细胞、中性粒细胞或淋巴细胞（及其亚群）的数量没有显著变化。出现了轻度单核细胞增多和嗜碱性粒细胞增多。治疗开始数小时出现的嗜酸性粒细胞减少之后是剂量和时间依赖性的嗜酸性粒细胞增多。IL-3治疗通过增加处于细胞周期S期的BM祖细胞百分比来影响BM细胞增殖。这种作用是剂量依赖性的，不同的祖细胞表现出不同程度的敏感性。最敏感的祖细胞是巨核细胞祖细胞（集落形成单位-巨核细胞），其次是红系祖细胞（爆式红系集落形成单位），最后是粒-单核祖细胞（集落形成单位-粒细胞-巨噬细胞），其增殖活性在较高剂量的IL-3作用下受到刺激。仅观察到成髓细胞、早幼粒细胞和中幼粒细胞的增殖活性略有增加，而成红细胞的活性未改变。这种启动作用使得从接受IL-3治疗的患者中纯化得到的BM祖细胞，在存在粒细胞集落刺激因子（G-CSF；粒细胞集落）、IL-5（嗜酸性粒细胞集落）和粒细胞-巨噬细胞集落刺激因子（GM-CSF；主要是嗜酸性粒细胞集落）的情况下，在体外产生更多的集落。这些数据表明，即使在体内，IL-3本质上也作为其他细胞因子作用的启动剂。因此，骨髓生成的最佳刺激将需要内源性或外源性的晚期作用细胞因子，如G-CSF、促红细胞生成素、GM-CSF和IL-6，以在外周血中获得完全成熟的细胞。如果将外源性细胞因子与IL-3一起使用，G-CSF可能会产生更多的中性粒细胞，而GM-CSF可能会增强嗜酸性粒细胞、单核细胞和中性粒细胞。有必要关注每种细胞类型的临床相关性，并应据此确定细胞因子组合的选择。
