泌尿系肿瘤治疗新策略-树突状细胞疫苗免疫治疗

树突状细胞(DC)作为目前已知的功能最强的抗原提呈细胞,也是抗原特异性免疫应答的始动者,可在体内外向T细胞提呈抗原并诱发CIL反应,在抗肿瘤免疫中发挥重要作用.近年来采用DC疫苗进行肿瘤免疫治疗研究获得一些突破性进展.本文就DC在肿瘤免疫中的作用机制、与泌尿系肿瘤免疫逃逸的关系、DC疫苗免疫治疗原理与制备方法及其在泌尿系肿瘤治疗方面的最新研究进展作一综述.     

泌尿系肿瘤治疗新策略—树突状细胞疫苗免疫治疗

树突状细胞（DC）作为目前已知的功能最强的抗原提呈细胞，也是抗原特异性免疫应答的初始者，可在体内外向T细胞提呈抗原并诱发CTL反应，在抗肿瘤免疫中发挥重要作用。近年来采用DC疫苗进行肿瘤免疫治疗研究获得一些突破性进展。本文就DC在肿瘤免疫中的作用机制、与泌尿系肿瘤免疫逃逸的关系、DC疫苗免疫治疗原理与制备方法及其在泌尿系肿瘤治疗方面的最新研究进展作一综述。     

基因修饰的树突状细胞疫苗诱导抗肿瘤免疫

树突状细胞是目前已知最有效的专职抗原提呈细胞,能诱导针对肿瘤的特异性细胞毒性T淋巴细胞反应,在抗肿瘤免疫中发挥着重要作用.运用树突状细胞的这一特性制备的肿瘤疫苗在体外和体内实验都已证明其抗肿瘤效应.近年来,基因修饰的树突状细胞疫苗由于其更出色的抗肿瘤效应成为研究的热点.本文就目前基因修饰的树突状细胞疫苗的研究现状,包括...     

DNA疫苗的研究进展

DNA疫苗是将携带抗原编码基因的质粒DNA直接注入动物体内,并在动物细胞中表达抗原蛋白以诱导动物产生免疫保护作用。DNA疫苗由载体质粒DNA内插入一个或多个抗原基因构成,主要通过肌肉注射或基因枪经皮内或皮下给予。接种后,质粒DNA被机体细胞摄取并表达相应抗原蛋白质,该蛋白质被专职抗原递呈细胞（professional antigen-presenting cell,APC）经MHC-Ⅰ类分子或MHC-Ⅱ类分子途径提呈给CD8^＋T细胞或CD4^＋T细胞,从而诱导细胞免疫和体液免疫。目前DNA疫苗在小动物身上已证明可有效应用于感染性疾病、肿瘤、自身免疫性疾病、过敏性疾病等,而且HIV、HBV、疟疾及某些肿瘤的DNA疫苗已进入临床试验并有一定疗效。尽管人们不乏有质粒DNA会整合入宿主的染色体,或者质粒DNA进入机体不诱导免疫反应而引起免疫耐受甚至产生自身免疫等担忧,但大量的实验研究及理论分析都基本肯定了DNA疫苗使用的安全性。只是DNA疫苗要想成为广泛应用于儿童和成人的一种安全有效的疫苗,还需要进行更谨慎、更系统的研究。     

树突状细胞与肺癌的疫苗治疗

树突状细胞是目前发现的功能最强的抗原提呈细胞,在机体抗肿瘤免疫中起重要作用。基于树突细胞而研制的肺癌肿瘤疫苗治疗是近年来肺癌治疗中异军突起的一种重要的辅助手段,有相当广阔的发展前景。     

树突状细胞疫苗与前列腺癌免疫治疗

目前治疗早期局限性前列腺癌的主要手段是手术切除和放射治疗 ,但其失败率超过 2 0 % 〔1〕 。不少患者于接受治疗时已经发展为转移性前列腺癌。在对于复发或转移性前列腺癌患者采取激素治疗、化疗、放疗治疗的疗效均不理想时 ,免疫治疗逐渐受到人们的重视 ,其中一个重要的方面就是树突状细胞 (ＤＣ)肿瘤疫苗的研究。肿瘤疫苗可以激活Ｔ细胞介导的免疫应答为主的机体抗肿瘤作用 ,使用自体或异体瘤苗 ,细胞溶解产物和肿瘤抗原的接种治疗可以产生一定的疗效 ,但效果不尽如人意。疗效不佳的一个重要原因被认为是由于抗原提呈系统的不足。ＤＣ细…     

避孕疫苗研究现状

人口过剩是严重的全球性问题 ,实行计划生育开发有效的避孕疫苗将成为控制人口增长的理想措施。目前已采用多种方法以确定能够用于发展避孕疫苗的特异性抗原 ,如 :精子抗原、ZP抗原、性激素抗原等 ,并已证实这些抗原在哺乳动物包括人类中可产生生殖抑制和免疫性避孕效应 ,目前正在积极支持进一步研究和开发这种有效的免疫性避孕疫苗。本文对免疫性避孕疫苗的开发及相关分子生物学技术的现状做一综述     

胰腺癌疫苗的研究(文献综述)

近年来研究较多的是IL 2、IFN γ、GM CSF基因修饰的胰腺癌细胞疫苗、DC疫苗、MUC 1或突变ras蛋白质 /多肽疫苗 ,而核酸疫苗研究刚起步。多数研究仍处于动物实验阶段 ,少部分进行了以晚期胰腺癌为对象的临床Ⅰ /Ⅱ期试验。研究发现 ,接种疫苗后出现较为明显的抗肿瘤免疫反应 ,并存在抗原特异的CTL应答。胰腺癌疫苗可能成为一种新的治疗手段 ,在未来胰腺癌的综合治疗中占一席之地。     

IL-23修饰的树突状细胞疫苗抗胰腺癌免疫应答的实验研究

树突状细胞（dendritic cells）是目前发现的功能最强大的肿瘤抗原专职递呈细胞。近年来负载肿瘤抗原的DC疫苗是抗肿瘤治疗的热点。白介素23（IL-23）是一种最新型的细胞因子，由P19及P40两条多肽链组成的异二聚体。IL-23可强化DC抗原递呈能力，使宿主针对肿瘤的免疫反应显著增强。     

树突状细胞疫苗在肾癌免疫治疗中的前景

树突状细胞 (DC)是体内专职的抗原提呈细胞 ,也是抗原特异性免疫应答的始动者 ,具有摄取、处理和提呈抗原至T细胞的功能 ,在抗肿瘤免疫中发挥重要作用。随着细胞生物学、分子生物学和免疫学等学科的飞速发展 ,以及新的实验体系和新的技术方法的不断涌现 ,使得树突状细胞在临床上应用 (尤其是抗肿瘤方面的应用 )的研究取得了日新月异的进展。本文主要对DC的生物特性、DC与肿瘤的关系及DC在肾癌免疫中的应用研究进展及前景作一综述     

Induction of PSA-specific CTLs and anti-tumor immunity by a genetic prostate cancer vaccine

BACKGROUND: Prostate cancer is the most common malignancy in Swedish and American men. Effective curative treatment modalities are debilitating and available only for localized disease. As an immunotherapy approach, DNA encoding prostate-specific antigen (PSA), was used to immunize mice and induce PSA-specific cellular immunity. METHODS: A plasmid expressing PSA, alone or in combination with plasmids coding for GM-CSF and/or IL-2, was used for DNA immunization. Cr-release, intracellular IFN-gamma cytokine staining, and tumor challenge assays were used to evaluate the immune response. RESULTS: The DNA vaccine induces PSA-specific cytotoxic T lymphocytes (CTLs) and when co-injected with IL-2 and GM-CSF it protects four of five mice against a PSA-expressing tumor challenge. CONCLUSIONS: We demonstrate that immunization with a PSA DNA vaccine can evoke PSA-specific cellular immune responses. We also show, for the first time, that a PSA DNA vaccine can induce anti-tumor immunity in vivo.     

Role of vaccine therapy for renal cell carcinoma in the era of targeted therapy

Renal cell carcinoma is the most common malignant tumor originating from the kidney. Compared with other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiotherapy. However, it is well known that renal cell carcinoma represents one of the most immune‐responsive cancers and several immunotherapeutic strategies have been investigated in the management of renal cell carcinoma with variable degrees of success. The development of immunotherapy with α‐interferon or high‐dose interleukin‐2 is the best established treatment, and is associated with durable disease control. Although the lack of defined antigens in renal cell carcinoma has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of renal cell carcinoma for more than 30 years. At present, there are three types of cell‐based vaccines in renal cell carcinoma treatment: autologous tumor‐cell vaccines, genetically modified tumor vaccines and dendritic cell‐based vaccines. A further type is peptide‐based vaccination with tumor‐associated antigens as possible targets, such as carbonic anhydrase IX, survivin and telomerase that are overexpressed in renal cell carcinoma. In the present article, we review data from completed clinical trials of vaccine therapy, and discuss future trials to assess the current knowledge and future role of vaccine therapy for renal cell carcinoma in the era of recently developed targeted therapy.     

转染干扰素-γ诱导蛋白-10基因构建树突状细胞前列腺癌瘤苗及其抗肿瘤免疫作用的检测

目的 将小鼠前列腺癌细胞株RM-1裂解产物加载树突状细胞(DC)后，转染干扰素-γ诱导蛋白-10(IP-10)基因构建DC瘤苗，探讨该瘤苗对小鼠抗肿瘤免疫反应的诱导作用。方法 将RM-1细胞的裂解产物作为肿瘤抗原加载小鼠骨髓来源的DC，并通过脂质体法转染IP-10基因，构建DC瘤苗；检测DC瘤苗的抗前列腺癌免疫治疗作用和免疫保护作用。结果 转染DC强表达IP-10，其上清对淋巴细胞有较强的趋化作用；构建的DC瘤苗能诱导特异性抗前列腺癌免疫反应，经瘤苗处理的荷瘤小鼠瘤体生长减慢，存活期延长；瘤苗还具有明显的免疫保护作用。结论 构建的前列腺癌DC瘤苗在体内能有效诱导抗肿瘤免疫反应和免疫保护功能。     

自体肿瘤疫苗治疗肝癌的实验研究

目的探讨自体肿瘤疫苗预防和治疗肝癌的效果及抗癌机制。方法采用多聚甲醛固定的小鼠Hepal-6细胞为抗原、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白介素-2（IL-2）缓释微球为免疫激活剂、辅以免疫辅助剂TiterMax Gold的肝癌疫苗皮内接种C57BL／6J小鼠，观察肿瘤疫苗预防和治疗肝癌的效果。结果对照组15只小鼠全部发展成肝肿瘤；含有固定Hepal6细胞和IL-2及GM—CSF微球的肿瘤疫苗，80％小鼠获得保护。再加入免疫辅助剂TiterMax Gold的肿瘤疫苗，则87％小鼠获得保护。将Hepal6细胞接种于左躯干皮下。肿瘤长至直径5mm时，皮内接种肿瘤疫苗2次。结果显示，对照组肿瘤继续生长。疫苗组在第2次接种后7～10d，肿瘤生长受到抑制，随后明显缩小。60％小鼠的肿瘤完全消失。细胞毒性实验结果显示，接种疫苗的小鼠脾细胞的杀瘤活性可被抗-CD3^＋、抗-CD8^＋、抗-MHC-Ⅰ单克隆抗体所阻断，但不被抗-CD4^＋、抗-MHC-Ⅱ单克隆抗体所阻断。结论自体肿瘤疫苗具有很强的抗肿瘤的效果。其抗瘤机制是诱导内源性抗原特异性CTL反应，由典型的MHC—Ⅰ限制的CD8^＋T细胞所介导的。     

自体瘤苗治疗肾癌的临床研究

目的探讨自体瘤苗治疗肾癌的临床应用价值。方法对３２例肾癌术后患者应用自体瘤苗,并与相应的对照组１９例进行比较,检测治疗前后外周血Ｔ细胞亚群ＣＤ３、ＣＤ４、ＣＤ８、ＣＤ４／ＣＤ８比值变化及ＮＫ细胞的活性。结果瘤苗组治疗后ＣＤ３、ＣＤ４、ＣＤ４／ＣＤ８较治疗前显著增加（Ｐ＜０．０１）,对照组无明显变化（Ｐ＞００５）。近期随诊也表明瘤苗组效果明显优于对照组。结论此疗法可以恢复肾癌患者受损的细胞免疫功能,提高肾癌病人的治疗效果。     

Development of a dendritic cell vaccine against measles for patients following hematopoietic cell transplantation

Most patients who have undergone hematopoietic cell transplantation (HCT) lose specific immunity to measles. However, due to its immunosuppressive potential, it has been recommended that a live attenuated measles vaccination be administered two years following HCT. Measles virus (MV) glycoproteins including hemagglutinin (HA) are expressed on MV-infected dendritic cells (DCs), and they impair efficient antigen presentation between the DC and T cell. We produced a DC-based vaccine against MV by loading DCs with MV-infected autologous DCs. MV in the infected DCs was inactivated using ultraviolet-B. The DC-based vaccine neither expressed HA nor inhibited allogeneic T cell proliferation, while it induced the production of interferon-gamma (IFN-gamma) by autologous CD4 and CD8 naive T cells ex vivo. Importantly, the vaccine derived from patients who had undergone HCT also efficiently induced IFN-gamma producing cells. These findings indicate that our DC-based MV vaccine induces MV-specific immunity even in post-HCT patients without causing immunosuppression.     

肝癌mRNA致敏的DC对SCID荷瘤鼠的抑瘤作用

目的通过重建人肝癌PBL-SCID嵌合模型来观察mRNA致敏的树突状细胞疫苗（mRNA DC）在体内的抑瘤效应并探讨机制。方法采用人外周血淋巴细胞腹腔注射法建立Hu-PBL-SCID鼠模型,尾静脉分别注射mRNA DC疫苗、抗CD4^＋、CD8^＋＋mRNA DC、未致敏的树突状细胞（DC）。每周1次,共两次,然后接种2×10^6HepG-2cells,观察鼠成瘤率、成瘤潜伏期、肿瘤体积以及测定特异性CTL活性。结果ELISA法可检测到鼠血清中人IgG水平,Hu-PBL-SCID嵌合模型重建成功,各组小鼠间成瘤率无明显差异,但mRNA DC组成瘤潜伏期延长,肿瘤生长缓慢,2周后肿瘤体积明显小于抗CD4^＋、CD8^＋＋mRNA DC组、DC组和PBS组,差异有统计学意义（P〈0.05）,实验组脾淋巴细胞对HepG-2细胞有特异性杀伤效应,而对胃癌SGC-7901细胞则无杀伤活性。结论mRNA致敏的树突状细胞疫苗体内能诱导产生明显的抑瘤作用。     

A novel dendritic cell-based cancer vaccine produces promising results in a syngenic CC-36 murine colon adenocarcinoma model

BACKGROUND: This study was conducted to test the efficacy of a new cancer vaccine, composed of dendritic cells (DCs) pulsed with an interleukin-2 gene-encoded vaccinia virus tumor oncolysate (DC-IL-2VCO) in a CC-36 murine colon adenocarcinoma model. MATERIALS AND METHODS: CC-36 tumor cells were injected subcutaneously into the left flank of four- to six-week old male BALB/c mice. The mice were divided into three groups, each of which received one of the following treatments: (1) DCs pulsed with the IL-2 gene-encoded vaccinia oncolysate (DC-IL-2VCO), (2) DCs pulsed with the tumor oncolysate alone (DC-CO), or (3) no treatment (control). Tumor incidence was measured, and survival rates were compared using a paired Student's t-test. Cytolytic T cell activity was measured in peripheral blood lymphocytes (PBL) and splenic lymphocytes using a (51)Cr-release assay. Lastly, mice were depleted of either CD4+ or CD8+ lymphocytes prior to receiving the vaccine to test the mechanism of tumor immunity in these mice. RESULTS: Mice treated with DC-IL-2VCO demonstrated decreased tumor burden, increased survival, and greater cytolytic activity compared with control mice and mice receiving DC-CO. In addition, mice depleted of CD8+ T cells prior to immunization with IL-2VV + DC-IL-2VCO had a significant increase in the incidence of tumor, similar to the untreated control mice. CONCLUSIONS: DCs pulsed with an IL-2 gene-encoded vaccinia virus tumor oncolysate (DC-IL-2VCO) produced safe and effective immune responses in a murine CC-36 colon adenocarcinoma model. This vaccine (DC-MelVac; Patent no. 11221/5) has the potential to treat humans with cancer, and has received FDA approval for use in Phase I clinical trials.     

Presentation of prostate tumor antigens by dendritic cells stimulates T-cell proliferation and cytotoxicity

Dendritic cells (DCs) are “professional” antigen-presenting cells capable of stimulating T-cell proliferation and cytotoxicity when loaded with and presenting specific antigens, including tumor antigens. We demonstrated the stimulation of an autologous cytotoxic T-cell response elicited by DC loaded with autologous tumor cell lysate derived from primary prostate tumor. A candidate tumor antigen is prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer patients. We identified a HLA-A2 motif in PSMA, isolated patient DC, loaded peptide into DC, and stimulated autologous T cells to proliferate. The ability to use DC for presentation of either tumor or peptide antigen in an HLA-restricted fashion in order to stimulate T-cell proliferation and cytotoxicity demonstrates the potential of this technology for development of a prostate cancer vaccine. © 1996 Wiley-Liss, Inc.     

单纯疱疹病毒疫苗的研究现状

单纯疱疹病毒(HSV)感染可以引起人类严重的复发性疾病并可在宿主中建立终生潜伏期,除此之外,尚能显著地增加人们感染人类免疫缺陷病毒(HIV)的机率,给患者带来严重的身心痛苦。尽管现存几种抗病毒疗法可以控制病毒的症状和传播,但却无法从根本上治愈或改变HSV感染的自然规律。因此,亟需研制一种有效的疫苗来控制HSV的感染、限制疾病的传播和复发。目前,研究较多且经过临床评估的疫苗主要有亚单位疫苗、减毒活疫苗、复制缺陷病毒疫苗、裸DNA疫苗以及载体疫苗,尽管它们中的一些在动物中可以诱发令人鼓舞的保护性免疫,但却没有一种可在人类中起到完全的预防或治疗作用,尽管如此,这些并未阻止学者对此疫苗的探索,本文就目前对HSV预防或治疗极具潜力的候选疫苗进行了综述。