Hammond Caitlin, Shi Yonghong, Mena Jenny, Tomic Jelena, Cervi David, He Liwei, Millar Amanda E, Debenedette Mark, Schuh Andre C, Baryza Jeremy L, Wender Paul A, Radvanyi Laszlo, Spaner David E
Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, 2075 Bayview Avenue, Toronto, Canada M4N 3M5.
J Immunother. 2005 Jan-Feb;28(1):28-39. doi: 10.1097/00002371-200501000-00004.
Since the intrinsically poor immunogenicity of chronic lymphocytic leukemia (CLL) cells might be a key factor in allowing them to avoid immune control mechanisms, the development of methods to enhance CLL cell immunogenicity might lead to improved disease control. The ability of CLL cells to stimulate T cells was increased significantly by the protein kinase C (PKC) agonist phorbol myristic acetate (PMA). However, under serum-free conditions, PMA-activated CLL cells died within 48 hours. Antioxidants, such as 2-mercaptoethanol (2-ME), or fetal calf serum could prevent the death of these cells but caused them to enter distinct states of differentiation. In the presence of 2-ME, PMA-activated CLL cells extended dendritic-like protrusions and exhibited increased T-cell stimulatory capacity. In the presence of serum, PMA-activated CLL cells developed fewer dendrites, made less IL-10 and more IL-12 p40 mRNA transcripts, and showed an increased capacity to induce IFN-gamma production by T cells. The effects of serum on the promotion of type 1 immune responses by phorbol ester-activated CLL cells were dominant and correlated with activation of the NF-kappaB signaling pathway. Other PKC agonists, such as Bryostatin-1 and a synthetic Bryostatin analog (Picolog), had similar effects on CLL cells. The observation that CLL cells can acquire features of dendritic cells that promote type 1 immunity may find clinical application in immunotherapeutic strategies for this disease.
由于慢性淋巴细胞白血病（CLL）细胞固有的免疫原性较差可能是其逃避免疫控制机制的关键因素，因此开发增强CLL细胞免疫原性的方法可能会改善疾病控制。蛋白激酶C（PKC）激动剂佛波醇肉豆蔻酸酯（PMA）可显著增强CLL细胞刺激T细胞的能力。然而，在无血清条件下，PMA激活的CLL细胞在48小时内死亡。抗氧化剂，如2-巯基乙醇（2-ME）或胎牛血清，可以防止这些细胞死亡，但会使它们进入不同的分化状态。在2-ME存在的情况下，PMA激活的CLL细胞伸出树突状突起，并表现出增强的T细胞刺激能力。在血清存在的情况下，PMA激活的CLL细胞形成的树突较少，产生的IL-10较少，IL-12 p40 mRNA转录本较多，并且显示出诱导T细胞产生IFN-γ的能力增强。血清对佛波酯激活的CLL细胞促进1型免疫反应的作用占主导地位，且与NF-κB信号通路的激活相关。其他PKC激动剂，如苔藓抑素-1和一种合成的苔藓抑素类似物（Picolog），对CLL细胞也有类似作用。CLL细胞可获得促进1型免疫的树突状细胞特征这一观察结果可能在该疾病的免疫治疗策略中具有临床应用价值。
