M2 Macrophages phagocytose Rituximab-Opsonized Leukemic Targets More Efficiently than M1 Cells In Vitro
M2 Macrophages phagocytose Rituximab-Opsonized Leukemic Targets More Efficiently than M1 Cells In Vitro
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DOI：
10.4049/jimmunol.0713732
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发表时间：
2009-04-01
影响因子：
4.4
通讯作者：
Golay, Josee
中科院分区：
文献类型：
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作者：
Leidi, Marzia;Gotti, Elisa;Golay, Josee
由于巨噬细胞在利妥昔单抗的作用机制中是主要参与者，我们研究了调节其肿瘤细胞杀伤潜力的因素。在使用利妥昔单抗调理的B-慢性淋巴细胞性白血病或淋巴瘤靶细胞的结合和吞噬测定中使用体外从外周血单核细胞分化的人巨噬细胞。吞噬作用在0.1 μ g/ml利妥昔单抗时达到最大，并且不受CD 20表达水平或CD 16 A 158位多态性（瓦尔/Phe）的显著影响。Fc γ R的作用通过过量人Ig对吞噬作用的完全抑制来证明。由于巨噬细胞可以分别用GM-CSF或M-CSF分化为M1或M2型细胞，并且可以通过促炎刺激（IFN-γ/LPS）经典地活化或用细胞因子如IL-4或IL-10进行替代活化，我们分析了这些不同极化程序对利妥昔单抗介导的吞噬作用的影响。与GM-CSF诱导的细胞相比，在M-CSF存在下分化的巨噬细胞显示出2至3倍的吞噬能力。此外，添加IL-10显著增加，而IL-4降低M-CSF和GM-CSF分化的巨噬细胞的吞噬作用。LPS/IFN-γ几乎没有影响。不同巨噬细胞群中CD 16、CD 32和CD 64的表达与吞噬活性相关。有趣的是，观察到几种B淋巴瘤细胞系在体外分泌400-1300 pg/ml IL-10，并且人巨噬细胞与淋巴瘤条件培养基共培养显著增加其吞噬能力。我们的数据表明，淋巴瘤细胞分泌的细胞因子可以有利于交替激活巨噬细胞对利妥昔单抗调理的目标具有高吞噬能力。免疫学杂志，2009，182：4415-4422.
Because macrophages have been implicated as major players in the mechanism of action of rituximab, we have investigated the factors that modulate their tumor cell killing potential. Human macrophages, differentiated in vitro from peripheral blood monocytes, were used in binding and phagocytosis assays using B-chronic lymphocytic leukemia or lymphoma target cells opsonized with rituximab. Phagocytosis was maximal at 0.1 mu g/ml rituximab and was not significantly affected by CD20 expression levels or by CD16A polymorphism at position 158 (Val/Phe). The role of Fc gamma Rs was demonstrated by complete inhibition of phagocytosis by excess human Igs. Because macrophages can be differentiated to M1- or M2-type cells with either GM-CSF or M-CSF, respectively, and can be classically activated by proinflammatory stimuli (IFN-gamma/LPS) or undergo alternative activation with cytokines such as IL-4 or IL-10, we have analyzed the effect of these different polarization programs on the phagocytosis mediated by rituximab. Macrophages differentiated in presence of M-CSF showed a 2- to 3-fold greater phagocytic capacity compared with GM-CSF-induced cells. Furthermore, addition of IL-10 significantly increased, whereas IL-4 decreased phagocytosis by both M-CSF- and GM-CSF-differentiated macrophages. LPS/IFN-gamma had little effect. Expression of CD16, CD32, and CD64 in different macrophage populations correlated with phagocytic activity. Interestingly, several B lymphoma cell lines were observed to secrete 400-1300 pg/ml IL-10 in vitro, and coculture of human macrophages with lymphoma conditioned medium increased significantly their phagocytic capacity. Our data suggest that cytokines secreted by lymphoma cells can favor alternate activation of macrophages with a high phagocytic capacity toward rituximab-opsonized targets. The Journal of Immunology, 2009, 182: 4415-4422.