Pinto A, Aldinucci D, Gloghini A, Zagonel V, Degan M, Perin V, Todesco M, De Iuliis A, Improta S, Sacco C, Gattei V, Gruss H J, Carbone A
Leukemia Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
Ann Oncol. 1997;8 Suppl 2:89-96.
Even though the presence of a prominent tissue eosinophilia represents a common histopathologic feature of Hodgkin's disease (HD), eosinophils have been mainly regarded as 'innocent' bystanders recruited and activated during the cellular reaction typical of HD. To evaluate the putative role of eosinophils or eosinophil-derived cytokines on tumor-cell regulation in HD, we have analyzed these cells for the functional expression of surface ligands (L) of the tumor necrosis factor (TNF) superfamily, whose specific receptors are known to transduce proliferation signals at the surface of Hodgkin (H) and Reed-Sternberg (RS) cells.
Eosinophils from peripheral blood of healthy donors and patients with HD, primary hypereosinophilic syndrome (HES), or secondary hypereosinophilia (HE), were purified by density gradient centrifugation and immunomagnetic depletion of residual granulocytes.
By immunostaining and mRNA analysis, we were able to show that eosinophils from normal donors and patients with HD, HES, and HE express a number of receptors and ligands of the TNF superfamily, including CD40, CD40L, CD30L, CD95/Fas, CD95/FasL and 4-1BB. In addition, we provide evidence that cytokines regulating eosinophil proliferation and activation, i.e., interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor, are able to enhance the cellular density of several TNF superfamily ligands and/or receptors at the surface of cultured eosinophils. Finally, we have shown that native CD40L and CD30L at the surface of purified eosinophils are functionally active and able to transduce proliferative signals on CD40+ and CD30+ target cells, including cultured H-RS cells.
Our data suggest that eosinophils may act as important elements in the pathology of HD by providing cellular ligands for TNF-superfamily receptors (CD40, CD30, CD95/Fas) able to transduce proliferation and antiapoptotic signals at the surface of H-RS cells. The presence on eosinophils of receptors for TNF ligands expressed by activated T cells (i.e., OX40L, FasL, CD40L, 4-1BBL), also suggest that eosinophils may contribute to the deregulated network of interactive signals between H-RS cells, T cells, and other surrounding reactive cells.
尽管显著的组织嗜酸性粒细胞增多是霍奇金淋巴瘤（HD）常见的组织病理学特征，但嗜酸性粒细胞主要被视为HD典型细胞反应过程中募集和激活的“无辜”旁观者。为了评估嗜酸性粒细胞或嗜酸性粒细胞衍生细胞因子在HD肿瘤细胞调控中的假定作用，我们分析了这些细胞肿瘤坏死因子（TNF）超家族表面配体（L）的功能表达，已知其特异性受体可在霍奇金（H）和里德-斯腾伯格（RS）细胞表面转导增殖信号。
通过密度梯度离心和对残留粒细胞的免疫磁珠清除法，从健康供体以及HD、原发性高嗜酸性粒细胞综合征（HES）或继发性嗜酸性粒细胞增多症（HE）患者的外周血中纯化嗜酸性粒细胞。
通过免疫染色和mRNA分析，我们能够证明来自正常供体以及HD、HES和HE患者的嗜酸性粒细胞表达多种TNF超家族的受体和配体，包括CD40、CD40L、CD30L、CD95/Fas、CD95/FasL和4-1BB。此外，我们提供证据表明调节嗜酸性粒细胞增殖和激活的细胞因子，即白细胞介素（IL）-5、IL-3和粒细胞-巨噬细胞集落刺激因子，能够增强培养的嗜酸性粒细胞表面几种TNF超家族配体和/或受体的细胞密度。最后我们表明，纯化的嗜酸性粒细胞表面的天然CD40L和CD30L具有功能活性，能够在包括培养的H-RS细胞在内的CD40+和CD30+靶细胞上转导增殖信号。
我们的数据表明，嗜酸性粒细胞可能通过为TNF超家族受体（CD40、CD30、CD95/Fas）提供细胞配体而在HD病理学中发挥重要作用，这些受体能够在H-RS细胞表面转导增殖和抗凋亡信号。嗜酸性粒细胞上存在由活化T细胞表达的TNF配体的受体（即OX40L、FasL、CD40L、4-1BBL），这也表明嗜酸性粒细胞可能有助于H-RS细胞、T细胞和其他周围反应性细胞之间失调的相互作用信号网络。
