IL—18的抗肿瘤作用

白细胞介素－18（IL－18）是近年发现的新型细胞因子,具有诱生IFN－γ,增强NK细胞活性,增强Th1型免疫反应,抗肿瘤作用等多种生物学功能,是一种应用前景较好的抗肿瘤细胞因子,综述IL－18的发现与来源,理化特性,生物学活性及抗肿瘤机理。     

白细胞介素-18及其抗肿瘤作用

白细胞介素-18（IL-18）是新近发现的一种多效能细胞因子，在刺激T细胞增殖，增强Th、细胞毒性T细胞和自然杀伤细胞等活性，抗肿瘤、免疫调节等方面有着积极的作用，有潜在广阔的应用前景。进一步研究IL-18抑制肿瘤的机制及其生物学作用具有重要的意义。     

白细胞介素-18与肿瘤免疫

肿瘤免疫治疗是近年来肿瘤治疗研究的热点,而作为其中的一项重要内容,细胞因子的基因治疗已经成为医学界关注的焦点。白细胞介素-18（IL-18）是具有多种生物学活性的新型多功能细胞因子,可以诱导IFN-γ的产生,增强NK和T细胞的活性,增强Th1型免疫反应,具有抗肿瘤、抗感染等生物学效应,对肿瘤具有预防和治疗作用。     

白细胞介素12抗肿瘤治疗进展

白细胞介素(IL)12是由巨噬细胞等抗原提呈细胞产生的具有多种生物学活性的异二聚体细胞因子,可刺激自然杀伤(NK)细胞、淋巴因子激活的杀伤细胞(LAK)细胞、细胞毒性T淋巴细胞(CTL)细胞的形成,增强机体对病原、肿瘤细胞的杀伤清除能力,诱导干扰素(INF)-γ、IL -2、IL-3、IL-8等细胞因子分泌和促进I型辅助性T细胞分化等多种生物学活性。国内外学者采用不同的治疗途径及不同的联合方案进行了大量尝试,以求获得最佳的抗肿瘤效应。     

IL-18基因修饰增强肿瘤细胞裂解物致敏的树突状细胞的抗肿瘤效应

目的:观察经肿瘤细胞裂解物致敏的白细胞介素18(IL-18)基因修饰的树突状细胞(DC)体内诱导的抗肿瘤免疫应答反应.方法:体外培养的小鼠骨髓树突状细胞经IL-18重组腺病毒感染后(IL18-DC),再经Hepal-6肝癌细胞裂解物冲击致敏后通过皮下注射用于荷瘤小鼠的治疗.用ELISA检测细胞因子,4 h51Cr释放法检测NK细胞活性及CTL杀伤活性.结果:致敏IL18-DC组体内诱导NK细胞活性与未致敏IL18-DC组无明显差别(P＞0.05),但明显高于致敏DC组和DC组(均P＜0.01);致敏IL18-DC组体内诱导特异性CTL杀伤活性明显高于IL18-DC组、致敏DC组和DC组(均P＜0.01);致敏IL18-DC组免疫治疗作用明显优于未致敏IL18-DC组、致敏DC组和DC组(均P＜0.01).结论:肿瘤细胞裂解物致敏的IL-18基因修饰的DC疫苗进行体内免疫治疗,能诱导出显著的抗肿瘤免疫反应,为DC介导的肿瘤基因治疗开辟了新的途径.     

肿瘤放免治疗后LAK细胞活性及IL—2R表达的改变及其与预后的关系

目的 本研究为了解放射免疫治疗是否可增强患者免疫活性细胞的功能,增强抗肿瘤效果。方法 检测21例恶性肿瘤患者接受放射免疫治疗当天、治疗后14天LAK细胞活性及白细胞介素—2受体(IL—2R)表达。结果 放免治疗后14天患者外周血LAK细胞活性增强,LAK细胞中IL—2R阳性细胞明显增加,治疗后显效组LAK细胞活性明显强于非显效组,IL—2R的表达也明显强于非显效组,而治疗前两组之间无明显差异。结论 认为放免治疗可增强机体免疫功能,且治疗的预后与LAK细胞的活性增强及IL—2R的表达密切相关。     

IL-2单独或联合IL-12活化骨髓抗肿瘤效应研究

目的 :研究白细胞介素 - 2 (IL - 2 )和白细胞介素 - 12 (IL - 12 )活化骨髓的抗肿瘤效应与重建造血功能 ;探讨活化骨髓的性质和杀伤肿瘤细胞的机制。方法 :测定活化骨髓杀伤肿瘤细胞的活性 ;检测活化骨髓的细胞表面分化抗原 ,特别是CD34 /CD38-细胞群的表达。结果 :活化骨髓与L12 10 细胞、新鲜白血病细胞共同培养后显示有杀伤肿瘤细胞作用 ,以培养 3～ 4天时最强 ;活化骨髓细胞的CD3、CD8、CD16、CD5 6分化抗原表达与新鲜骨髓相比升高 ,有显著性差异 (P <0 0 1)。L12 10 细胞、新鲜白血病细胞与活化骨髓共同培养后分化抗原CD71、CD95表达下降 ,超二倍体、亚二倍体等异倍体减少 ,与对照组相比有显著性差异 (P <0 0 5 ) ;活化骨髓中CD34 /CD38-细胞分化抗原表达与新鲜骨髓相比没有显著性差异 (P >0 0 5 )。IL - 12活化骨髓效靶比 (E∶T)稀释一倍后杀伤白血病细胞活性仍然比IL - 2活化骨髓明显 ;IL - 2联合IL - 12诱导后活化骨髓抗肿瘤活性进一步增强。结论 :活化骨髓具有抗肿瘤效应 ,其中有细胞毒T细胞、自然杀伤细胞的作用 ,也有凋亡机制参与 ;活化骨髓还保留有重建造血的功能 ;IL - 12活化骨髓比IL - 2活化骨髓的活性高 ;且IL - 2联合IL - 12诱导后活化骨髓抗肿瘤活性进一步增强     

白细胞介素12抗肿瘤治疗进展

白细胞介素（IL）12是由巨噬细胞等抗原提呈细胞产生的具有多种生物学活性的异二聚体细胞因子,可刺激自然杀伤（NK）细胞、淋巴因子激活的杀伤细胞（LAK）细胞、细胞毒性T淋巴细胞（cTL）细胞的形成,增强机体对病原、肿瘤细胞的杀伤清除能力,诱导干扰素（INF）-γ、IL-2、IL-3、IL-8等细胞因子分泌和促进Ⅰ型辅助性T细胞分化等多种生物学活性。国内外学者采用不同的治疗途径及不同的联合方案进行了大量尝试,以求获得最佳的抗肿瘤效应。     

榄香烯乳胸腔灌注对恶性胸水渗出液相关淋巴细胞(EAL)增殖及其LAK活性的增强作用实验研究

作者研究了榄香烯乳胸腔灌注对恶性胸水中渗出液相关淋巴细胞（EAL）的增殖和LAK活性的影响。结果显示，榄香烯乳能够明显促进EAL细胞增殖共产生显著的LAK活性，榄香烯乳还具有增强IL－2诱导的EAL细胞增殖效应及其LAK活性的作用，提示榄香烯乳与IL－2联合应用有可能产生增效作用。榄香烯乳的抗肿瘤免疫机制可能是通过作用于IL－2R／IL－2系统激活EAL细胞而发挥其抗肿瘤作用。结果提示，榄香烯乳有希望成为一种新型免疫增强剂而扩大应用于恶性肿瘤的免疫治疗。     

IL_2的抗肿瘤作用

近年来,从免疫调节角度考虑,可使用免疫调节分子来防治肿瘤,干扰素是众所周知的一个例子。IL2(白细胞间介素2,Inter-leukin 2)为引人注目的一种抗肿瘤的免疫调节分子。本文在介绍IL2的基础上,对1980年以来有关IL2抗肿瘤的文献做一综述。IL2的理、化、生物学性能     

In vivo and in vitro characteristics of interleukin 6-transfected B16 melanoma cells.

Interleukin 6 (IL-6) is a multifunctional cytokine important in the inflammatory response. Its potential role as an antitumor agent has been suggested by its demonstrated activity in a variety of tumor models. The mechanism of antitumor activity has been proposed to be its enhancement of cytotoxic T-cell function. In the current work we demonstrate clear antitumor activity for this cytokine in a nonimmunogenic tumor system. B16 melanoma cells transfected with the human IL-6 complementary DNA demonstrated slower tumor growth in vivo. Tumors that developed from these cells had a prominent stromal matrix, an easily recognized infiltration of inflammatory cells, fewer mitotic figures, and fewer blood vessels. These in vivo findings corresponded with a greater adhesion of the IL-6-transfected B16 cells to stromal matrix proteins (laminin, fibronectin, and vitronectin) and a less prominent vascular response in an intradermal angiogenesis assay. Therefore, we propose that with weakly antigenic tumors, such as B16 melanoma, IL-6 may mediate important antitumor responses by nonspecific proinflammatory mechanisms.     

Immunomodulatory and antitumor effects of interleukin-21 in patients with renal cell carcinoma

Interleukin (IL)-21 is a class I cytokine with sequence homology to the IL-2 cytokine superfamily. IL-21 signals through a heterodimer of a unique IL-21 receptor and the common γ-chain cytokine receptor. Preclinical murine models suggested strong antitumor activity of IL-21 in renal cell carcinoma, melanoma and other tumor models. IL-21 antitumor activity was superior to IL-2 in these tumor models. A Phase I clinical trial of IL-21 in humans with metastatic renal cell carcinoma or melanoma began in May 2004. Clinical regressions were observed in renal cell carcinoma. Preliminary immunological and clinical findings of patients receiving IL-21 will be reviewed.     

Immunomodulatory and antitumor effects of interleukin-21 in patients with renal cell carcinoma

Interleukin (IL)-21 is a class I cytokine with sequence homology to the IL-2 cytokine superfamily. IL-21 signals through a heterodimer of a unique IL-21 receptor and the common gamma-chain cytokine receptor. Preclinical murine models suggested strong antitumor activity of IL-21 in renal cell carcinoma, melanoma and other tumor models. IL-21 antitumor activity was superior to IL-2 in these tumor models. A Phase I clinical trial of IL-21 in humans with metastatic renal cell carcinoma or melanoma began in May 2004. Clinical regressions were observed in renal cell carcinoma. Preliminary immunological and clinical findings of patients receiving IL-21 will be reviewed.     

Interleukin 18 transfection enhances antitumor immunity induced by dendritic cell-tumor cell conjugates

Dendritic cell (DC)-based tumor vaccine represents a promising approach to the immunotherapy of malignant tumors. We prepared a novel type of DC-based vaccine, stable conjugates of DCs and EL4 cells transduced with cDNA of OVA (E.G7). Immunization with DC-E.G7 conjugates led to generation of T helper (Th) 1 cytokine-producing cells, antigen-specific CD8(+) T cells, and strong antitumor immunity that is dependent on both CD4(+) T cells and CD8(+) T cells. To further increase the potency of the vaccine, interleukin 18-transfected DCs were used to prepare the IL18DC-E.G7 conjugates. Immunization with such conjugates significantly increased the production of Th1 cytokine-producing cells and the number of antigen-specific CD8(+) T cells, as well as stronger antitumor immunity. Furthermore, the increased Th1 cytokine production and stronger antitumor effect were not observed in mice depleted of IFN-gamma. These data indicated that DC-tumor cell conjugates are a potent tumor vaccine. Interleukin 18 can be administrated using gene-transfected cells and enhances antitumor immunity, which is mainly mediated by IFN-gamma.     

白介素12抗肿瘤作用的研究进展

白介素 - 12 (IL 12 )是一种异源二聚体细胞因子 ,被认为是细胞免疫应答过程中的关键调节因子。IL 12能激活NK细胞、T细胞 ,并诱使其分泌大量IFN γ ,抑制肿瘤血管生成 ,对多种肿瘤的预防和治疗显示了良好的应用前景。综述了IL 12及其抗肿瘤方面的研究进展。     

Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL-18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro-IL-18) in vitro. In addition, IL-18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL-18 is increased in EOC patients' sera at diagnosis as compared with age-matched healthy women. IL-18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL-18 expression in cytokeratine-positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL-18. The detection of human IL-18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL-18 is tumor-derived. However, IL-18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL-18 present in the ascitic fluid as pro-IL-18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL-18 levels. Altogether these data indicate that IL-18 in EOC fluids is predominantly tumor-derived and that its lack of biological activity may represent a mechanism of tumor-escape.     

Overexpression of interleukin-15 in vivo enhances antitumor activity against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response

Interleukin (IL)-15, a pleiotropic cytokine, is involved in the development and maintenance of NK cells and memory CD8+ T cells. We examined the effects of in vivo overexpression of IL-15 on protection against 2 types of murine B16 melanoma lines, MHC class I-negative B16.44 and MHC class I-positive B16F10 cells, using IL-15 transgenic (Tg) mice that we have recently constructed. The tumor growth was severely retarded in IL-15 Tg mice after subcutaneous (s.c.) inoculation with B16.44 or B16F10 cells. IL-15 Tg mice showed an augmented NK cell activity against B16.44 cells, and in vivo depletion of NK cells by anti-asialoGM1 Ab treatment abrogated the antitumor activity in IL-15 Tg mice. On the other hand, IL-15 Tg mice inoculated with B16F10 cells developed a significant level of CTL response against B16F10 cells, and in vivo depletion of CD8+ T cells by anti-CD8 MAb treatment abrogated the antitumor activity. Thus, overexpression of IL-15 augmented antitumor activity against different tumors via augmentation of different antitumor mechanisms. These results suggest a possible therapeutic application of IL-15 for human neoplasms expressing a wide range of MHC class molecules.     

Ex vivo culture with interleukin (IL)-12 improves CD8(+) T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-gamma but requires perforin

In animal models and clinical trials, adoptive transfer of activated, antigen-specific CD8(+) T cells mediates tumor regression in a cell dose-dependent manner. The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Activated ovalbumin-specific CD8(+) T cells cultured with IL-12, IL-18, both, or neither were assayed for antigen-specific cytokine production and cytolytic activity and adoptively transferred to C57BL/6 mice with established tumors. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure. T cells cultured with IL-12 more effectively eliminated tumors, and addition of IL-18 did not further augment responses. IFN-gamma-deficient CD8(+) T cells showed effective antitumor activity that was enhanced by IL-12 with or without IL-18. Perforin-deficient CD8(+) T cells were poor mediators of antitumor activity, though, and showed no improvement after culture with IL-12 and/or IL-18. Thus, ex vivo culture with IL-12 was sufficient to augment antigen-specific in vitro cytotoxicity and antitumor activity in vivo in an IFN-gamma-independent but perforin-dependent manner. Ex vivo culture with IL-12 may improve CD8(+) T-cell immunotherapy of cancer in the absence of donor cell-derived IFN-gamma via perforin-mediated cytolysis.     

Fusokine interleukin-2/interleukin-18, a novel potent innate and adaptive immune stimulator with decreased toxicity

To redress the immune imbalances created by pathologies such as cancer, it would be beneficial to create novel cytokine molecules, which combine desired cytokine activities with reduced toxicities. Due to their divergent but complementary activities, it is of interest to combine interleukin-2 (IL-2) and IL-18 into one recombinant molecule for immunotherapy. Evaluation of a fusokine protein that combines murine IL-2/IL-18 shows that it is stable, maintains IL-2 and IL-18 bioactivities, has notably reduced IL-2 associated toxicities, and has a novel lymphocyte-stimulating activity. An adeno-viral expression system was used to explore the biology of this "fusokine". Inclusion of the IL-18 prosequence (proIL-18) increases the expression, secretion, and potency of this fusokine. In vivo gene transfer experiments show that Ad-IL-2/proIL-18 dramatically outdoes Ad-IL-2, Ad-proIL-18, or the combination of both, by inducing high rates of tumor rejection in several murine models. Both innate and adaptive effector mechanisms are required for this antitumor activity.