ULBPs及MIC分子在亚健康状态诊断及评价中的作用

 目的 建立亚健康状态人群ULBPs和MICA/B分子表达数据库,分析它们作为亚健康状态的具体参考指标的可能。方法 采用体检和问卷调查的方法对志愿者进行筛查,然后通过酶联免疫技术对收集的样本进行ULBPs和MICA/B血清含量的检测。结果 亚健康组的MICA,MICB,ULBP1和ULBP2的平均值均高于健康对照组,ULBP3,ULBP4和ULBP5的亚健康组平均值均低于健康对照组。单因素分析和多因素logistic回归分析都显示亚健康组和健康组之间只有MICB有显著性差别(P<0.01)。另外,男性MICA和ULBP3的平均值高于女性,且两组间有显著性差别。而ULBP2和ULBP4会随着年龄的增长呈现上升趋势。结论 亚健康组的血清MICB含量明显升高,它可以联合其他免疫指标一起作为诊断亚健康的一种辅助手段。     

人类自然杀伤细胞活化性配体ULBPs的表达与调控

人类自然杀伤细胞活化性配体UL16结合蛋白(UL16-binding proteins,ULBPs)家族至少由6个成员组成,其中ULBP1、ULBP2、ULBP3(ULl6-binding protein 1-3)分子含有α1和α2结构域,通过糖基磷脂酰肌醇(giycosylphosphatidylinositol,GPI)与细胞膜相连。ULBP4(UL16-binding protein 4)分子含有跨膜和胞质结构域。正常组织中广泛表达ULBPs。T淋巴细胞瘤、结肠癌、卵巢癌等肿瘤细胞表面也有ULBPs的高表达。化学药物、细胞因子、细菌和病毒感染等众多因素都可以调控ULBPs的表达,其中紫外线辐射、化疗药物等诱发的DNA损伤反应可以活化3-磷脂酰肌醇激酶家族类成员(ataxia-telangiecta- sia mutated,ATM)或(ataxia-telangiectasia and Rad3-related,ATR)激酶,进一步活化下游的Chk1、Chk2节点激酶和其他的凋亡相关分子,从而诱导ULBPs的表达,引起肿瘤细胞的生长周期停滞,诱导细胞凋亡,发挥抗肿瘤作用。另外,ULBP1启动子中CRE1位点活化也是上调ULBP1转录和表达的关键因素。对ULBPs表达与调控因素的深入探讨将为阐明肿瘤逃逸机制、寻求抗肿瘤有效药物提供新的作用靶点和思路。     

NKG2D signaling in cancer immunosurveillance

The immune system is able to detect and eliminate transformed cells. The activating receptor NKG2D is particularly relevant for cancer immunosurveillance. NKG2D ligand expression renders tumor cells more susceptible to be killed by NK and T cells, and correlates with the clinical outcome of the disease. However, tumors develop mechanisms to overcome the NKG2D‐mediated immune response, which has been associated with poor prognosis and impairment of the clinical benefits of immunotherapy in many human cancers. The highly specific pattern of expression displayed by the NKG2D ligands, mainly confined to tumor cells, together with the strong immune response triggered by this receptor clearly supports the idea that the NKG2D‐mediated pathway may be a powerful target for the treatment of cancer. This review draws together the most recent discoveries concerning the biology of the NKG2D signaling and their therapeutic relevance in the context of cancer.     

Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer

To develop more effective therapies for patients with advanced gastric cancer, we examined the potential of ex vivo expanded natural killer (NK) cells. We assessed the expression of ligands for NK Group 2 Member D (NKG2D, an important NK activation molecule) in primary tumors from 102 patients with gastric cancer by immunohistochemistry and determined their prognostic value. We then examined the in vitro and in vivo cytotoxicity of NK cells from healthy donors and patients with gastric cancer. The cytotoxicity of resting and of interleukin (IL)‐2‐activated NK cells was compared to that of NK cells expanded for 7 days by coculture with the K562‐mb15‐4.1BBL cell line. As a result, the expression of NKG2D ligands in primary tumors was correlated with favorable presenting features and outcomes, suggesting that gastric cancer may be sensitive to NK cell cytotoxicity. Although resting NK cells showed minimal cytotoxicity against gastric cancer cells, K562‐mb15‐4.1BBL‐expanded NK cells were highly cytotoxic and significantly more powerful than IL‐2‐activated NK cells. Cytotoxicity was correlated with NKG2D ligand expression and could be modulated by mitogen‐activated protein kinase and AKT‐PI3 kinase inhibitors. The cytotoxicity of expanded NK cells against HER2‐positive gastric cancer cells could be increased by Herceptin and further augmented by Lapatinib. Finally, expanded NK cells exhibited strong antitumor activity in immunodeficient mice engrafted with a gastric cancer cell line. In conclusion, gastric cancer tumors express NKG2D ligands and are highly susceptible to killing by NK cells stimulated by K562‐mb15‐4.1BBL. These results provide a strong rationale for clinical testing of these NK cells in patients and suggest their use to augment the effects of antibody therapy.     

自然杀伤细胞受体家族NKG2D研究进展

NKG2D是自然杀伤细胞的一种激活性受体 ,与其配体MICA和MICB结合后 ,在多肽DAP 10P的介导下激活自然杀伤细胞 ,导致表达MHC和MICA/B分子的靶细胞被杀伤 ,在肿瘤的免疫监视中发挥重要的作用。UL16结合蛋白 (ULBPs)是NKG2D的另一种新的配体分子 ,在病毒感染及人类巨细胞病毒逃脱免疫监视过程中可能起着重要作用