负载肿瘤抗原的树突状细胞疫苗联合CpG-ODN对膀胱肿瘤免疫治疗效应的实验研究
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摘要
膀胱肿瘤是国内泌尿系最常见肿瘤,其最主要的临床特点是发病率高、复发率高。膀胱肿瘤的发生和复发主要与机体免疫功能低下、肿瘤细胞逃逸机体的免疫监视有关,如何提高膀胱肿瘤患者的免疫功能成为治疗和预防膀胱肿瘤复发的关键。
树突状细胞(DC)是目前发现的体内功能最强,也是唯一能激活初始型T淋巴细胞的抗原递呈细胞(APC)。近年来随着人们了解的深入,基于DC的肿瘤免疫治疗方法越来越受关注。负载肿瘤抗原的DC具有疫苗的功能,故称之为树突状细胞疫苗。由于DC疫苗有较高的抗原递呈效率,正成为新一代疫苗的代表。围绕DC开展的以DC为基础的肿瘤免疫治疗正成为目前肿瘤治疗的热点。
自从Tokunaga等发现从卡介苗(BCG)中提取的DNA片段具有抗肿瘤活性后,人们对细菌DNA的作用进行了深入研究。研究发现,细菌DNA具有强大的免疫刺激活性,其基础是以未甲基化胞嘧啶鸟嘌呤(CpG)二核苷酸为核心的六碱基序列。人工合成的含CpG序列的寡脱氧核糖核苷酸(CpG-ODN)具有与细菌DNA相同的免疫活性,与DC表面TLR-9受体特异性结合,激活DC,上调共刺激分子的表达、增强DC向T细胞递呈抗原的能力,分泌Th1型细胞因子及趋化因子,由此产生第二效应,活化NK细胞及单核细胞,发挥抗肿瘤能力。CpG-ODN使用安全,未见有明显副作用,因此CpG-ODN作为一种新的免疫佐剂有望在临床中得到应用。
目前CpG-ODN联合抗体、细胞因子治疗肿瘤的研究已逐步展开,但联合DC疫苗的研究国内外较少,尤其是在膀胱肿瘤的研究未见报道。本研究首先探讨了膀胱移行细胞癌(BTCC)组织中浸润性DC(TIDC)的功能状态在膀胱癌免疫逃逸中的作用,然后观察了CpG-ODN诱导小鼠骨髓来源的DC成熟的作用,并制备了负载小鼠BTT739肿瘤细胞抗原的DC疫苗,研究了DC疫苗联合CpG-ODN在体内外对膀胱肿瘤细胞的免疫学效应。实验分三部分进行,主要研究内容及结果如下:
第一部分树突状细胞在膀胱癌中的浸润及其意义
目的探讨DC在膀胱癌中的浸润及其在膀胱癌免疫逃逸中的作用。
方法采用免疫组织化学SP法及流式细胞仪检测36例膀胱移行细胞癌(BTCC)
Bladder tumor is the most common tumor in urinary system of domestic people, which is characterized as high incidence rate and high recurrence rate in clinic. The devolpment and recurrence of bladder tumor is related to the low immunological function of host. How to raise the immunological function of patients with bladder cancer is the key to treat and prevent recurrence of bladder tumor.
Dendritic cells are believed to have the most powerful antigen presenting capacity and the native T cells can be only primed by DC. With the intensive understanding to the biological behaviors of DC, people pay more and more attention to the role of DC in cancer immune therapy. Dendritic cell-based vaccine manifests a good clinical applications as a representative of new vaccines
Recent studies have shown that immunostimulatory activity of Bacillus Calmette-Guerin resides in its DNA fraction and that unmethylated CpG motifs in bacterial DNA are responsible for this activity. Synthetic oligodeoxynucleotides(ODNs) containing CpG motifs have the same activity as bacterial DNA. CpG-ODNs are recognized by specific Toll-like receptor 9 on the surface of DCs and induce an activataion phenotype of DCs characterized by the expression of costimulatory molecules, enhanced antigen presentation to T cells and secretion of T helper 1 (Th1)-promoting chemokins and cytokines, which trigger a wide range of secondary effects, such as natural killer(NK) cell and monocyte activation, which have antitumor activity. As a new immune adjuvant, CpG-ODN may be used in clinic because of high effectiveness and safety
For immunotherapy of tumors, CpG-ODN have been successfully used in combination with tumor-specific antibodies and cytokines as a vaccine adjuvant, but is seldomly combined with DC-based vaccine, especially in baldder tumor. In the present study, we investigated firstly the functional status of tumor infiltrating dendritic cells (TIDC) in bladder cancer. Secondly, the effect of CpG-ODN on activating DCs was evaluated. After
树突状细胞(DC)是目前发现的体内功能最强,也是唯一能激活初始型T淋巴细胞的抗原递呈细胞(APC)。近年来随着人们了解的深入,基于DC的肿瘤免疫治疗方法越来越受关注。负载肿瘤抗原的DC具有疫苗的功能,故称之为树突状细胞疫苗。由于DC疫苗有较高的抗原递呈效率,正成为新一代疫苗的代表。围绕DC开展的以DC为基础的肿瘤免疫治疗正成为目前肿瘤治疗的热点。
自从Tokunaga等发现从卡介苗(BCG)中提取的DNA片段具有抗肿瘤活性后,人们对细菌DNA的作用进行了深入研究。研究发现,细菌DNA具有强大的免疫刺激活性,其基础是以未甲基化胞嘧啶鸟嘌呤(CpG)二核苷酸为核心的六碱基序列。人工合成的含CpG序列的寡脱氧核糖核苷酸(CpG-ODN)具有与细菌DNA相同的免疫活性,与DC表面TLR-9受体特异性结合,激活DC,上调共刺激分子的表达、增强DC向T细胞递呈抗原的能力,分泌Th1型细胞因子及趋化因子,由此产生第二效应,活化NK细胞及单核细胞,发挥抗肿瘤能力。CpG-ODN使用安全,未见有明显副作用,因此CpG-ODN作为一种新的免疫佐剂有望在临床中得到应用。
目前CpG-ODN联合抗体、细胞因子治疗肿瘤的研究已逐步展开,但联合DC疫苗的研究国内外较少,尤其是在膀胱肿瘤的研究未见报道。本研究首先探讨了膀胱移行细胞癌(BTCC)组织中浸润性DC(TIDC)的功能状态在膀胱癌免疫逃逸中的作用,然后观察了CpG-ODN诱导小鼠骨髓来源的DC成熟的作用,并制备了负载小鼠BTT739肿瘤细胞抗原的DC疫苗,研究了DC疫苗联合CpG-ODN在体内外对膀胱肿瘤细胞的免疫学效应。实验分三部分进行,主要研究内容及结果如下:
第一部分树突状细胞在膀胱癌中的浸润及其意义
目的探讨DC在膀胱癌中的浸润及其在膀胱癌免疫逃逸中的作用。
方法采用免疫组织化学SP法及流式细胞仪检测36例膀胱移行细胞癌(BTCC)
Bladder tumor is the most common tumor in urinary system of domestic people, which is characterized as high incidence rate and high recurrence rate in clinic. The devolpment and recurrence of bladder tumor is related to the low immunological function of host. How to raise the immunological function of patients with bladder cancer is the key to treat and prevent recurrence of bladder tumor.
Dendritic cells are believed to have the most powerful antigen presenting capacity and the native T cells can be only primed by DC. With the intensive understanding to the biological behaviors of DC, people pay more and more attention to the role of DC in cancer immune therapy. Dendritic cell-based vaccine manifests a good clinical applications as a representative of new vaccines
Recent studies have shown that immunostimulatory activity of Bacillus Calmette-Guerin resides in its DNA fraction and that unmethylated CpG motifs in bacterial DNA are responsible for this activity. Synthetic oligodeoxynucleotides(ODNs) containing CpG motifs have the same activity as bacterial DNA. CpG-ODNs are recognized by specific Toll-like receptor 9 on the surface of DCs and induce an activataion phenotype of DCs characterized by the expression of costimulatory molecules, enhanced antigen presentation to T cells and secretion of T helper 1 (Th1)-promoting chemokins and cytokines, which trigger a wide range of secondary effects, such as natural killer(NK) cell and monocyte activation, which have antitumor activity. As a new immune adjuvant, CpG-ODN may be used in clinic because of high effectiveness and safety
For immunotherapy of tumors, CpG-ODN have been successfully used in combination with tumor-specific antibodies and cytokines as a vaccine adjuvant, but is seldomly combined with DC-based vaccine, especially in baldder tumor. In the present study, we investigated firstly the functional status of tumor infiltrating dendritic cells (TIDC) in bladder cancer. Secondly, the effect of CpG-ODN on activating DCs was evaluated. After
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