Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice
Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice
复制标题
DOI：
10.1182/blood.v90.12.4779.4779_4779_4788
复制
发表时间：
1997-12-15
期刊：
影响因子：
20.3
通讯作者：
Papayannopoulou, T
中科院分区：
文献类型：
--
作者：
Craddock, CF;Nakamoto, B;Papayannopoulou, T
尽管细胞因子动员的外周血干细胞的使用在临床移植中获得了巨大的动力，但所实施的动员方案受到大量经验主义的指导。细胞因子或趋化因子单独或组合导致干细胞/祖细胞从骨髓重新分布到外周血的机制尚不清楚。同样，动员的干/祖细胞的命运及其生物学特性也没有完全确定。解释细胞因子诱导动员机制的主要假设之一包括细胞因子直接或间接破坏干/祖细胞与其骨髓基质的细胞粘附相互作用的观点。与这一观点相一致的是几种细胞粘附分子（尤其是整联蛋白）的表达和/或功能的变化、动员后以及支持细胞因子[整联蛋白相互作用的概念的广泛体外实验。为了进一步了解细胞因子/整合素在体内的相互作用，我们将细胞因子治疗与抗整合素治疗结合起来，用于灵长类动物和小鼠的动员。我们发现抗VLA4治疗与粒细胞集落刺激因子（G-CSF）治疗或试剂盒配体治疗相结合可显着提高动员效率（五倍至八倍），远高于单独细胞因子或单独抗VLA4治疗产生的水平。当细胞因子的组合，即G-CSF加试剂盒配体或G-CSF加Flt3配体与抗-VLA4在灵长类动物和小鼠中使用时，观察到类似的增强。此外，当在5-氟尿嘧啶治疗的灵长类动物中给予抗VLA4时，仅在抗VLA4治疗的动物中，在恢复期间，大量的祖细胞循环了数天。这些数据表明（1）抗VLA4对动员的影响，当单独使用时，不太可能由体内次级细胞因子的加工介导； (2)三种不同的细胞因子及其组合似乎不影响共同给药方案中对抗VLA4的体内反应性； 13)即使细胞因子治疗本身下调VLA4功能，受抗VLA4或细胞因子影响的靶祖细胞也不一定重叠； (4)细胞因子/抗VLA4治疗中动员的增强很可能是由抗VLA4发挥作用的靶细胞库的扩增引起的。因为细胞因子或抗 VLA4 均能够动员长期重新增殖的细胞，并且因为我们目前的研究表明，在自体骨髓细胞移植环境中抗 VLA4 不会导致任何植入延迟，因此增强动员的细胞因子/抗整合素治疗的组合可能具有临床用途。 (C) 1997 年，美国血液学会。
Although the use of cytokine-mobilized peripheral blood stem cells has gained a significant momentum in clinical transplantation, the mobilization schemes practiced are guided by a great deal of empiricism. The mechanism(s) by which cytokines or chemokines, alone or in combination, bring about redistribution of stem/progenitor cells from bone marrow to peripheral blood are poorly understood. Likewise the fate of mobilized stem/progenitor cells and their biological properties are incompletely defined. One of the leading hypotheses to explain the mechanism of cytokine-induced mobilization encompasses the view that cytokines disrupt, directly or indirectly, cytoadhesive interactions of stem/progenitor cells with their bone marrow stroma. Compatible with this view are changes in the expression and/or function of several cytoadhesion molecules, especially integrins, postmobilization, and extensive in vitro experimentation supporting the concept of cytokine[integrin interactions. To provide a further insight on the cytokine/integrin interplay in vivo, we have combined cytokine treatments with anti-integrin treatments for mobilization in primates and mice. We found that anti-VLA4 treatment combined with either granulocyte colony-stimulating factor (G-CSF) treatment or kit ligand treatment leads to significant enhancement of mobilization efficiency (fivefold to eight-fold) well above the levels produced by either cytokine alone or anit-VLA4 treatment alone. Similar enhancement was seen when combinations of cytokines, ie, G-CSF plus kit ligand or G-CSF plus Flt3-ligand were used with anti-VLA4 in primates and mice. Furthermore, when anti-VLA4 was given in 5-Fluorouracil-treated primates, significant numbers of progenitor cells were circulating for several days during the recovery period only in the anti-VLA4 treated animals. These data suggest that (1) the effect of anti-VLA4 on mobilization, when used alone, is unlikely to be mediated by secondary cytokine elaboration in vivo; (2) three different cytokines and their combinations do not appear to influence the in vivo responsiveness to anti-VLA4 in coadministration schemes; 13) even if cytokine treatments on their own exert downmodulation of VLA4 function, the target progenitor cells influenced by anti-VLA4 or by cytokines may not necessarily overlap; and (4) augmentation of mobilization in cytokine/anti-VLA4 treatments is most likely caused by an amplification of the pool of target cells on which anti-VLA4 exerts its effects. Because cytokines or anti-VLA4 are each capable of mobilizing long-term repopulating cells and because we show with the present studies that anti-VLA4 in an autologous bone marrow cell transplantation setting does not cause any delay ih engraftment, the combination of cytokine/anti-integrin treatment enhancing mobilization may have a clinical use. (C) 1997 by The American Society of Hematology.