MUC1模拟表位肽疫苗预防和治疗膀胱癌的实验研究
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摘要
目的:观察MUC1糖链和肽链表位在肾脏和膀胱肿瘤中的表达,筛选MUC1糖链表位的模拟肽,研究模拟表位肽疫苗诱导T739小鼠产生功能性免疫应答及预防和治疗膀胱癌的作用。
材料与方法:1)免疫组化二步法检测MUC1糖链和肽表位在肾癌及膀胱癌中的表达、分布及其与细胞类型、肿瘤分期分级的关系;2)筛选噬菌体随机12肽库,获得与识别MUC1糖链表位的单克隆抗体Ma695结合的模拟肽;流式细胞仪鉴定模拟肽的竞争抑制效应;分离小鼠脾脏单个核细胞,在GM-CSF和IL-4条件下培养获得树突状细胞,LPS促其成熟,FCM鉴定其纯度;负载模拟肽的成熟树突状细胞免疫T739小鼠后,用ELISA、ELISPOT等方法观察模拟肽诱导与原表位交叉反应的体液免疫应答和特异性细胞免疫应答;非放射性乳酸脱氢酶法检测体外细胞毒活性;3)利用脂质体介导的方法,在BST739中转入人MUC1全长cDNA,经G418筛选和克隆化培养,建立稳定表达MUC1的T739小鼠膀胱癌细胞亚系BST739-MUC1,PCR、RT-PCR、免疫组化、激光共聚焦显微镜、流式细胞仪、免疫印迹等鉴定MUC1基因和蛋白的表达及分布,观察转入人MUC1对肿瘤细胞黏附和体内外生长的影响;4)建立小鼠膀胱移行细胞癌预防和治疗模型,观察模拟表位肽疫苗的预防和治疗作用。
结果:1)MUC1在85.5%的肾脏肿瘤和100%的移行细胞癌中表达,阳性细胞数及分布模式与肿瘤分期分级相关。2)筛选噬菌体随机肽库获得MUC1糖链表位的模拟表位肽M1,能竞争抑制Ma695与MUC1+肿瘤细胞MCF7的结合。当细胞数为2×10~5、Ma695浓度为0.25μg/ml、M1肽浓度为100、200、400、800μg/ml时,抑制率分别为11%、26%、26%和34%;脾脏单个核细胞培养7天获得具有典型形态特征的树突状细胞,FCM显示其纯度为83.2%;负载M1肽的DC免疫小鼠后,诱导特异性CTL应答,ELISPOT结果表明,活化的特异性T细胞为脾脏淋巴细胞的116/10~6;同
Purpose 1) To observe the expression profile of MUC1 peptide andcarbohydrate epitopes in renal cell carcinoma (RCC) and bladder transitional cell carcinoma(TCC) . 2) To biopan phage displayed random peptide library to get peptides that mimic MUCl sialylated carbohydrate epitope and to preliminarily investigate the functional immunological responses induced with the mimotope and its effectiveness in prevention and treatment of MUC1-positive bladder TCC .Materials and Methods 1). The expression and distribution pattern of MUC1 carbohydrate and peptide epitopes were detected with immunohistochemistry, so as to their correlation with pathological grade and clinical stages. 2). Phage displayed random peptide library was biopanned to get 12-mer peptides that might mimic MUC1 sialylated carbohydrate epitope, which regcognized specifically by monoclonal antibody Ma695. Competitive inhibition assay by flowcytometry analysis with MUC1-positive tumor cell MCF7 was done to confirm the specificity of the peptide mimics. Dendritic cells were derived from mice mono-nuclear cells of splenocytes with GM-CSF and IL-4 and matured with LPS, the purity of DC was identified by FCM. Antibody responses cross-reacting with MUC1-positive tumor cells and mimotope-specific CTL response in mice immunized with mimotope-containing peptide pulsed DCs were studied with flowcytometry, ELISA and ELISPOT. In vitro CTL response was analyzed by non-radiative LDH cytotoxicity analysis. 3) Mice bladder TCC sub-cell line expressing human MUC1,designated BST739-MUC1, was established by Lipofectamine-mediated transfection of human MUC1 full length cDNA into BST739 cells, followed by G418
selection and clonal culturing. PCR, RT-PCR, immunohistochemistry, confocal imaging, flowcytometry and Western blotting were carried out to confirm the stable integration of MUC 1 cDNA into the mouse genome and expression of MUCl mRNA and proteins in the cells. The in vitro adhesive and growth characteristics of BST739-MUC1, as well as its in vivo tumorigenicity were also investigated. 4) The preventive and therapeutic mice models of bladder TCC were established to investigate preliminarily the effectiveness of MUCl mimotope-containing peptide as a tumor vaccine in the inhibition of MUCl-positive tumor cells growth in vivo. Results 1) The expression of MUClwas detected in 85.5% of RCCand 100% of TCC. The percentage of positive cells and their distribution model were closely correlated with pathological grade and clinical stages. 2) Ml-peptide that mimic MUCl carbohydrate epitope was obtained through a 3-round biopanning of phage displayed random 12-mer peptide library. Ml inhibited the binding of McAb Ma695 to MCF7 competitively. As the cell number (2xlO5) and the concentration of Ma695(0.25ug/ml) were fixed, when the concentration of Ml was 100 ug/ml ,200 ug/ml, 400 ug/ml and 800 ug/ml, the inhibition rate was 11%, 26%, 26% and 34%, respectively. After a 6-day culture and 1-day maturation with LPS, cells with characteristic appearance of mature DC were harvested, FCM showed that 83.2% cells expressed a marker of mature DC. Ml-specific CTL could be induced with Ml-pulsed DC, as the results of ELISPOT showed that the frequency of functional T cells (IFN-ysecreting lymphocytes determined in ELISPOT) in immunized mice was 116/105 spleen cells. Also, specific antibody responses induced by Ml-pulsed DC, which could cross-react with MUCl carbohydrate epitope, were detected and the FCM results showed that serum from immunized mice could react with MUC 1-positive tumor cells, but not MUCl-negtive ones. 3) The MUCl gene integration, transcription and protein expression in BST739-MUC1 were confirmed by
genomic DNA PCR, RT-PCR, immunohistochemistry and Western-blotting, Confocal imaging indicated that MUCl protein expressed in the cell membranes as well as in the cytoplasm. Compared with BST739, the in vitro adhesion rate of BST739-MUC1 increased by 44% through MTT assay. The syngeneic mice would reject MUCl-positive tumor cells, for this reason, the in vivo growth of BST739-MUC1 had a characteristic of fast-slow-fast fashion. During the first 18 days after inoculation, the growing speed of BST739-MUC1 was much faster. On the 18th day, the volume of BST739-MUC1 tumor was 2744±948mm3 vs 808±322mm\ p=0.0013) , and then the growth rate was slowed down during the 18th to 26th day and from the 26th day on, the growth rate accelerated again. 4). Splenocytes of mice immunized with Ml-pulsed DC showed antitumor reactivity in vitro, as determined by CTL analysis. The splenocytes could kill 18.9%~29.5% BST739-MUC1 when the E/T ratio was 100:1. In the preventive model, tumor weight of mice immunized with Ml-pulse DC was only 14.4%(1.7±0.8mg vs 11.8±4.8 mg, p O.001) of that in the control group. Ml-reacting antibody concentration increased from 0.57±0.21 to 1.52±0.54(167% increase)and CTL reactivity increased by 122%(17.3% vs 7.8%). In the therapeutic model, the life duration of mice challenged with 2xlO6 BST739-MUC1 and then treated with Ml-pulse DC prolonged 50%(44±5.7days vs 30±1.6days, p=0.0031) , the concentration of Ml-reacting antibody showed a 338% (1.71 vs 0.39) increase and a 71% (19.5% vs 11.4%) increase of the CTL reactivity was also observed. Conclusions 1) Over-expression and aberrant distribution of MUCl were common in RCC and TCC, indicating that MUCl was an ideal target for antitumor vaccine of these malignant tumors. 2) Mice bladder cancer cell line BST739-MUC1 stably expressed human MUCl and BST739-MUC1 -associated tumor models were established. 3) 12-mer peptide Ml that mimic MUCl carbohydrate epitope was identified and cellular and
材料与方法:1)免疫组化二步法检测MUC1糖链和肽表位在肾癌及膀胱癌中的表达、分布及其与细胞类型、肿瘤分期分级的关系;2)筛选噬菌体随机12肽库,获得与识别MUC1糖链表位的单克隆抗体Ma695结合的模拟肽;流式细胞仪鉴定模拟肽的竞争抑制效应;分离小鼠脾脏单个核细胞,在GM-CSF和IL-4条件下培养获得树突状细胞,LPS促其成熟,FCM鉴定其纯度;负载模拟肽的成熟树突状细胞免疫T739小鼠后,用ELISA、ELISPOT等方法观察模拟肽诱导与原表位交叉反应的体液免疫应答和特异性细胞免疫应答;非放射性乳酸脱氢酶法检测体外细胞毒活性;3)利用脂质体介导的方法,在BST739中转入人MUC1全长cDNA,经G418筛选和克隆化培养,建立稳定表达MUC1的T739小鼠膀胱癌细胞亚系BST739-MUC1,PCR、RT-PCR、免疫组化、激光共聚焦显微镜、流式细胞仪、免疫印迹等鉴定MUC1基因和蛋白的表达及分布,观察转入人MUC1对肿瘤细胞黏附和体内外生长的影响;4)建立小鼠膀胱移行细胞癌预防和治疗模型,观察模拟表位肽疫苗的预防和治疗作用。
结果:1)MUC1在85.5%的肾脏肿瘤和100%的移行细胞癌中表达,阳性细胞数及分布模式与肿瘤分期分级相关。2)筛选噬菌体随机肽库获得MUC1糖链表位的模拟表位肽M1,能竞争抑制Ma695与MUC1+肿瘤细胞MCF7的结合。当细胞数为2×10~5、Ma695浓度为0.25μg/ml、M1肽浓度为100、200、400、800μg/ml时,抑制率分别为11%、26%、26%和34%;脾脏单个核细胞培养7天获得具有典型形态特征的树突状细胞,FCM显示其纯度为83.2%;负载M1肽的DC免疫小鼠后,诱导特异性CTL应答,ELISPOT结果表明,活化的特异性T细胞为脾脏淋巴细胞的116/10~6;同
Purpose 1) To observe the expression profile of MUC1 peptide andcarbohydrate epitopes in renal cell carcinoma (RCC) and bladder transitional cell carcinoma(TCC) . 2) To biopan phage displayed random peptide library to get peptides that mimic MUCl sialylated carbohydrate epitope and to preliminarily investigate the functional immunological responses induced with the mimotope and its effectiveness in prevention and treatment of MUC1-positive bladder TCC .Materials and Methods 1). The expression and distribution pattern of MUC1 carbohydrate and peptide epitopes were detected with immunohistochemistry, so as to their correlation with pathological grade and clinical stages. 2). Phage displayed random peptide library was biopanned to get 12-mer peptides that might mimic MUC1 sialylated carbohydrate epitope, which regcognized specifically by monoclonal antibody Ma695. Competitive inhibition assay by flowcytometry analysis with MUC1-positive tumor cell MCF7 was done to confirm the specificity of the peptide mimics. Dendritic cells were derived from mice mono-nuclear cells of splenocytes with GM-CSF and IL-4 and matured with LPS, the purity of DC was identified by FCM. Antibody responses cross-reacting with MUC1-positive tumor cells and mimotope-specific CTL response in mice immunized with mimotope-containing peptide pulsed DCs were studied with flowcytometry, ELISA and ELISPOT. In vitro CTL response was analyzed by non-radiative LDH cytotoxicity analysis. 3) Mice bladder TCC sub-cell line expressing human MUC1,designated BST739-MUC1, was established by Lipofectamine-mediated transfection of human MUC1 full length cDNA into BST739 cells, followed by G418
selection and clonal culturing. PCR, RT-PCR, immunohistochemistry, confocal imaging, flowcytometry and Western blotting were carried out to confirm the stable integration of MUC 1 cDNA into the mouse genome and expression of MUCl mRNA and proteins in the cells. The in vitro adhesive and growth characteristics of BST739-MUC1, as well as its in vivo tumorigenicity were also investigated. 4) The preventive and therapeutic mice models of bladder TCC were established to investigate preliminarily the effectiveness of MUCl mimotope-containing peptide as a tumor vaccine in the inhibition of MUCl-positive tumor cells growth in vivo. Results 1) The expression of MUClwas detected in 85.5% of RCCand 100% of TCC. The percentage of positive cells and their distribution model were closely correlated with pathological grade and clinical stages. 2) Ml-peptide that mimic MUCl carbohydrate epitope was obtained through a 3-round biopanning of phage displayed random 12-mer peptide library. Ml inhibited the binding of McAb Ma695 to MCF7 competitively. As the cell number (2xlO5) and the concentration of Ma695(0.25ug/ml) were fixed, when the concentration of Ml was 100 ug/ml ,200 ug/ml, 400 ug/ml and 800 ug/ml, the inhibition rate was 11%, 26%, 26% and 34%, respectively. After a 6-day culture and 1-day maturation with LPS, cells with characteristic appearance of mature DC were harvested, FCM showed that 83.2% cells expressed a marker of mature DC. Ml-specific CTL could be induced with Ml-pulsed DC, as the results of ELISPOT showed that the frequency of functional T cells (IFN-ysecreting lymphocytes determined in ELISPOT) in immunized mice was 116/105 spleen cells. Also, specific antibody responses induced by Ml-pulsed DC, which could cross-react with MUCl carbohydrate epitope, were detected and the FCM results showed that serum from immunized mice could react with MUC 1-positive tumor cells, but not MUCl-negtive ones. 3) The MUCl gene integration, transcription and protein expression in BST739-MUC1 were confirmed by
genomic DNA PCR, RT-PCR, immunohistochemistry and Western-blotting, Confocal imaging indicated that MUCl protein expressed in the cell membranes as well as in the cytoplasm. Compared with BST739, the in vitro adhesion rate of BST739-MUC1 increased by 44% through MTT assay. The syngeneic mice would reject MUCl-positive tumor cells, for this reason, the in vivo growth of BST739-MUC1 had a characteristic of fast-slow-fast fashion. During the first 18 days after inoculation, the growing speed of BST739-MUC1 was much faster. On the 18th day, the volume of BST739-MUC1 tumor was 2744±948mm3 vs 808±322mm\ p=0.0013) , and then the growth rate was slowed down during the 18th to 26th day and from the 26th day on, the growth rate accelerated again. 4). Splenocytes of mice immunized with Ml-pulsed DC showed antitumor reactivity in vitro, as determined by CTL analysis. The splenocytes could kill 18.9%~29.5% BST739-MUC1 when the E/T ratio was 100:1. In the preventive model, tumor weight of mice immunized with Ml-pulse DC was only 14.4%(1.7±0.8mg vs 11.8±4.8 mg, p O.001) of that in the control group. Ml-reacting antibody concentration increased from 0.57±0.21 to 1.52±0.54(167% increase)and CTL reactivity increased by 122%(17.3% vs 7.8%). In the therapeutic model, the life duration of mice challenged with 2xlO6 BST739-MUC1 and then treated with Ml-pulse DC prolonged 50%(44±5.7days vs 30±1.6days, p=0.0031) , the concentration of Ml-reacting antibody showed a 338% (1.71 vs 0.39) increase and a 71% (19.5% vs 11.4%) increase of the CTL reactivity was also observed. Conclusions 1) Over-expression and aberrant distribution of MUCl were common in RCC and TCC, indicating that MUCl was an ideal target for antitumor vaccine of these malignant tumors. 2) Mice bladder cancer cell line BST739-MUC1 stably expressed human MUCl and BST739-MUC1 -associated tumor models were established. 3) 12-mer peptide Ml that mimic MUCl carbohydrate epitope was identified and cellular and
引文
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62. Cao Y, Karsten U, Zerban H, et al. Expression of MUC1, Thomsen- Friedenreich-related antigens, and cytokeratin 19 in human renal cell carcinomas and tubular clear cell lesions Virchows Arch. 2000; 436(2): 119-26
63.Kraus S, Abel PD, Nachtmann C, et al. MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis. Hum Pathol. 2002 ;33(1):60-7
64. Bryan RT, Nicholls JH, Harrison RF, et al. The role of beta-catenin signaling in the malignant potential of cystitis glandularis. J Urol. 2003 ;170(5): 1892-6
65. Pantuck AJ, Bancila E, Das KMl,et al.Adenocarcinoma of the urachus and bladder expresses a unique colonic epithelial epitope: an immunohistochemical study. J Urol. 1997 ; 158(5): 1722-7
66. Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA. 1999; 96(10): 5522-7.
67.Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin Dl in colon carcinoma cells. Nature. 1999;398(6726):422-6.
68. Roose J, Huls G, van Beest M, et al. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcfl. Science. 1999; 285(5435): 1923-6.
69. Wen Y, Caffrey TC, Wheelock MJ, et al. Nuclear association of the cytoplasmic tail of MUC1 and beta-catenin. J Biol Chem. 2003; 278(39): 38029-39.
70. Siriaunkgul S, Tavassoli FA Invasive micropapillary carcinoma of the
breast. Mod Pathol. 1993 Nov;6(6):660-2
71. Nassar H, Pansare V, Zhang H, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUCl glycoprotein. Mod Pathol. 2004; 17(9): 1045-50
72. Kontani K, Taguchi O, Narita T, et al.Modulation of MUCl mucin as an escape mechanism of breast cancer cells from autologous cytotoxic T-lymphocytes. Br J Cancer. 2001 ;84(9): 1258-64
73. Liu M, Acres B, Balloul JM, et al. Gene-based vaccines and immunotherapeutics. Proc Natl Acad Sci USA. 2004 ;101 (Suppl 2): 14567-71.
74. McCool TL, Harding CV, Greenspan NS, et al. B- and T-cell immune responses to pneumococcal conjugate vaccines: divergence between carrierand polysaccharide-specific immunogenicity Infect Immun. 1999; 67(9): 4862-9
75.Kitamura K, Stockert E, Garin-Chesa P, et al. Specificity analysis of blood group Lewis-y (Le(y)) antibodies generatedagainst synthetic and natural Le(y) determinants. Proc Natl Acad Sci USA. 1994 ; 91(26): 12957-61.
76. Cunto-Amesty G, Luo P, Monzavi-Karbassi B, et al. Exploiting molecular mimicry to broaden the immune response to carbohydrate antigens for vaccine development Vaccine. 2001; 19( 17-19):2361 -8
77. Apostolopoulos V, Lofthouse SA, Popovski V, et al. Peptide mimics of a tumor antigen induce functional cytotoxic T cells Nat Biotechnol. 1998; 16(3):276-80.
78. Luo P, Canziani G, Cunto-Amesty G, et al. A molecular basis for functional peptide mimicry of a carbohydrate antigen J Biol Chem. 2000; 275(21):16146-54
79. Gundlach BR, Wiesmuller KH, Junt T, et al. Determination of T cell epitopes with random peptide libraries J Immunol Methods. 1996;
192(1-2):149-55.
80.Walden P. T-cell epitope determination.Curr Opin Immunol. 1996;8(1):68-74.
81. La Rosa C, Krishnan R, Markel S, et al. Enhanced immune activity of cytotoxic T-lymphocyte epitope analogs derived from positional scanning synthetic combinatorial libraries. Blood. 2001; 97(6): 1776-86
81.Clay TM, Custer MC, McKee MD, et al. Changes in the fine specificity of gp100(209-217)-reactive T cells in patients following vaccination with a peptide modified at an HLA-A2.1 anchor residue. J Immunol. 1999; 162(3): 1749-55
82.Udaka K, Wiesmuller KH, Kienle S, et al. Self-MHC-restricted peptides recognized by an alloreactive T lymphocyte clone. J Immunol. 1996; 157(2):670-8
83.Staveley-O'Carroll K, Sotomayor E, Montgomery J, et al. Induction of antigen-specific T cell anergy: An early event in the course of tumor progression : Proc Natl Acad Sci USA. 1998;95(3): 1178-83.
84. Sparbier K, Walden P T. cell receptor specificity and mimotopes Curr Opin Immunol. 1999 ; 11(2): 214-8.
85. Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on virion surface. Science 1985;228:1315-1317.
86.Sibille P ,Strosberg AD. A FIV epitope defined by a phage peptide library screened with a monoclonal anti-FIV antibody. Immunol Lett 1997;59: 133-137
87.Burton R. Phage display.Immunotechnol 1995;1(2):87-94. Stephen B,Gershoni JM.Construction and use of a 20-mer phage display epitope library .Methods Mol Bio 1998;87:137-154
88. Devlin JJ,Panganiban LC,Devlin PE,et al.Random peptide library:a source of specific protein binding molecule.Science 1990;249(96):404-406
89. Szardenings M, Tornroth S, Mutulis F, et al. Phage display selection on
whole cells yields a peptide specific for melanocortin receptor 1. J Biol Chem. 1997; 272 (44) : 27943-8
90. Lowman HB. Phage display of peptide libraries on protein scaffolds. Methods Mol Biol. 1998; 87: 249-64
91. Klein J, Sato A. The HLA system. First of two parts. N Engl J Med. 2000 7; 343 (10) : 702-9
92. Klein J, Sato A. The HLA system. Second of two parts. N Engl J Med. 2000 14; 343 (11) : 782-6
93. Huang AY, Golumbek P, Ahmadzadeh M, et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science. 1994; 264 (5161) : 961-5
94. Pittet MJ, Zippelius A, Speiser DE, et al. Ex vivo IFN-gamma secretion by circulating CD8 T lymphocytes: implications of a novel approach for T cell monitoring in infectious and malignant diseases. J Immunol. 2001; 166 (12) : 7634-40.
95.张吉凤,台桂香,赵雷等.鼠与人MUC1分子同源性位点的分析.免疫学杂志,2003,19(2):83-85
96. Dai J, Allard WJ, Davis G, et al. Effect of desialylation on binding, affinity, and specificity of 56 monoclonal antibodies against MUC1 mucin. Tumour Biol. 1998; 19 (Suppl 1) : 100-10.
97. Young AC, Valadon P, Casadevall A, et al. The three-dimensional structures of a polysaccharide binding antibody to Cryptococcus neoformans and its complex with a peptide from a phage display library: implications for the identification of peptide mimotopes. J Mol Biol. 1997; 274 (4) : 622-34
98. Werdelin O, Meldal M, Jensen T. Processing of glycans on glycoprotein and glycopeptide antigens in antigen-presenting cells. Proc Natl Acad Sci U S A. 2002; 99 (15) : 9611-3.
99. Monzavi-Karbassi B, Cunto-Amesty G, Luo P, Shamloo S, Blaszcyk-Thurin M, Kieber-Emmons T. Immunization with a carbohydrate mimicking peptide augments tumor-specific cellular responses. Int Immunol. 2001;13(ll):136I-71.
100. Wang HY, Fu T, Wang G, Zeng G, et al. Induction of CD4(+) T cell-dependent antitumor immunity by TAT-mediated tumor antigen delivery into dendritic cells. J Clin Invest. 2002 Jun;109(11):1463-70.
101. Eguchi A, Akuta T, Okuyama H, et al. Protein transduction domain of HIV-1 Tat protein promotes efficient delivery of DNA into mammalian cells. J Biol Chem. 2001;276(28):26204-10
102. Spicer AP, Parry G, Patton S, et al. Molecular cloning and analysis of the mouse homologue of the tumor-associated mucin, MUC1, reveals conservation of potential O-glycosylation sites, transmembrane, and cytoplasmic domains and a loss of minisatellite-like polymorphism. J Biol Chem. 1991;266(23): 15099-109.
103. Lalani EN, Berdichevsky F, Boshell M, et al. Expression of the gene coding for a human mucin in mouse mammary tumor cells can affect their tumorigenicity. J Biol Chem. 1991;266(23):15420-6
104. Rowse GJ, Tempero RM, VanLith ML, et al. Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model. Cancer Res. 1998;58(2):315-21
105. Apostolopoulos V, Xing PX, McKenzie IF. Murine immune response to cells transfected with human MUC1: immunization with cellular and synthetic antigens. Cancer Res. 1994;54( 19):5186-93
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45. Zhang K, Baeckstrom D, Brevinge H, et al. Secreted MUC1 mucins lacking their cytoplasmic part and carrying sialyl-Lewis a and x epitopes from a tumor cell line and sera of colon carcinoma patients can inhibit HL-60 leukocyte adhesion to E-selectin-expressing endothelial cells. J Cell Biochem. 1996;60(4):538-49
46. Gendler SJ. MUC1, the renaissance molecule. J Mammary Gland Biol Neoplasia. 2001;6(3):339-53
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53. Hudson MJ, Stamp GW, Chaudhary KS, et al. Human MUC1 mucin: a potent glandular morphogen. J Pathol. 2001;194(3):373-383
54. Rahn JJ, Dabbagh L, Pasdar M, et al. The importance of MUC1 cellular localization in patients with breast carcinoma: an immunohistologic study of 71 patients and review of the literature. Cancer, 2001;91:973-1982
55. Ioannides CG, Fisk B, Jerome KR, et al. Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides. J Immunol. 1993;151(7):3693-703
56.Jerome KR, Barnd DL, Bendt KM, et al. Cytotoxic T-lymphocytes derived from patients with breast adenocarcinoma recognize an epitope present on the protein core of a mucin molecule preferentially expressed by malignant cells. Cancer Res. 1991;51(11):2908-16
57. Gourevitch MM, von Mensdorff-Pouilly S, Litvinov SV, et al. Polymorphic epithelial mucin (MUC-l)-containing circulating immune complexes in carcinoma patients. Br J Cancer. 1995;72(4):934-8
58. Strokel S, Eble JN, Adlakha K, et al. Classification of renal cell carcinoma. Cancer, 1997;80(5):987-989
59. Leroy X, Zini L, Leteurtre E, et al. Morphologic subtyping of papillary renal cell carcinoma: correlation with prognosis and differential expression of MUC1 between the two subtypes. Mod Pathol. 2002;15(ll):1126-30
60. Fujita K, Denda K, Yamamoto M, et al. Expression of MUC1 mucins inversely correlated with post-surgical survival of renal cell carcinoma
patients. Br J Cancer. 1999;80(l-2):301-8
61. Leroy X, Copin MC, Devisme L, et al. Expression of human mucin genes in normal kidney and renal cell carcinoma. Histopathology. 2002;40(5):450-7.
62. Cao Y, Karsten U, Zerban H, et al. Expression of MUC1, Thomsen- Friedenreich-related antigens, and cytokeratin 19 in human renal cell carcinomas and tubular clear cell lesions Virchows Arch. 2000; 436(2): 119-26
63.Kraus S, Abel PD, Nachtmann C, et al. MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis. Hum Pathol. 2002 ;33(1):60-7
64. Bryan RT, Nicholls JH, Harrison RF, et al. The role of beta-catenin signaling in the malignant potential of cystitis glandularis. J Urol. 2003 ;170(5): 1892-6
65. Pantuck AJ, Bancila E, Das KMl,et al.Adenocarcinoma of the urachus and bladder expresses a unique colonic epithelial epitope: an immunohistochemical study. J Urol. 1997 ; 158(5): 1722-7
66. Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA. 1999; 96(10): 5522-7.
67.Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin Dl in colon carcinoma cells. Nature. 1999;398(6726):422-6.
68. Roose J, Huls G, van Beest M, et al. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcfl. Science. 1999; 285(5435): 1923-6.
69. Wen Y, Caffrey TC, Wheelock MJ, et al. Nuclear association of the cytoplasmic tail of MUC1 and beta-catenin. J Biol Chem. 2003; 278(39): 38029-39.
70. Siriaunkgul S, Tavassoli FA Invasive micropapillary carcinoma of the
breast. Mod Pathol. 1993 Nov;6(6):660-2
71. Nassar H, Pansare V, Zhang H, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUCl glycoprotein. Mod Pathol. 2004; 17(9): 1045-50
72. Kontani K, Taguchi O, Narita T, et al.Modulation of MUCl mucin as an escape mechanism of breast cancer cells from autologous cytotoxic T-lymphocytes. Br J Cancer. 2001 ;84(9): 1258-64
73. Liu M, Acres B, Balloul JM, et al. Gene-based vaccines and immunotherapeutics. Proc Natl Acad Sci USA. 2004 ;101 (Suppl 2): 14567-71.
74. McCool TL, Harding CV, Greenspan NS, et al. B- and T-cell immune responses to pneumococcal conjugate vaccines: divergence between carrierand polysaccharide-specific immunogenicity Infect Immun. 1999; 67(9): 4862-9
75.Kitamura K, Stockert E, Garin-Chesa P, et al. Specificity analysis of blood group Lewis-y (Le(y)) antibodies generatedagainst synthetic and natural Le(y) determinants. Proc Natl Acad Sci USA. 1994 ; 91(26): 12957-61.
76. Cunto-Amesty G, Luo P, Monzavi-Karbassi B, et al. Exploiting molecular mimicry to broaden the immune response to carbohydrate antigens for vaccine development Vaccine. 2001; 19( 17-19):2361 -8
77. Apostolopoulos V, Lofthouse SA, Popovski V, et al. Peptide mimics of a tumor antigen induce functional cytotoxic T cells Nat Biotechnol. 1998; 16(3):276-80.
78. Luo P, Canziani G, Cunto-Amesty G, et al. A molecular basis for functional peptide mimicry of a carbohydrate antigen J Biol Chem. 2000; 275(21):16146-54
79. Gundlach BR, Wiesmuller KH, Junt T, et al. Determination of T cell epitopes with random peptide libraries J Immunol Methods. 1996;
192(1-2):149-55.
80.Walden P. T-cell epitope determination.Curr Opin Immunol. 1996;8(1):68-74.
81. La Rosa C, Krishnan R, Markel S, et al. Enhanced immune activity of cytotoxic T-lymphocyte epitope analogs derived from positional scanning synthetic combinatorial libraries. Blood. 2001; 97(6): 1776-86
81.Clay TM, Custer MC, McKee MD, et al. Changes in the fine specificity of gp100(209-217)-reactive T cells in patients following vaccination with a peptide modified at an HLA-A2.1 anchor residue. J Immunol. 1999; 162(3): 1749-55
82.Udaka K, Wiesmuller KH, Kienle S, et al. Self-MHC-restricted peptides recognized by an alloreactive T lymphocyte clone. J Immunol. 1996; 157(2):670-8
83.Staveley-O'Carroll K, Sotomayor E, Montgomery J, et al. Induction of antigen-specific T cell anergy: An early event in the course of tumor progression : Proc Natl Acad Sci USA. 1998;95(3): 1178-83.
84. Sparbier K, Walden P T. cell receptor specificity and mimotopes Curr Opin Immunol. 1999 ; 11(2): 214-8.
85. Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on virion surface. Science 1985;228:1315-1317.
86.Sibille P ,Strosberg AD. A FIV epitope defined by a phage peptide library screened with a monoclonal anti-FIV antibody. Immunol Lett 1997;59: 133-137
87.Burton R. Phage display.Immunotechnol 1995;1(2):87-94. Stephen B,Gershoni JM.Construction and use of a 20-mer phage display epitope library .Methods Mol Bio 1998;87:137-154
88. Devlin JJ,Panganiban LC,Devlin PE,et al.Random peptide library:a source of specific protein binding molecule.Science 1990;249(96):404-406
89. Szardenings M, Tornroth S, Mutulis F, et al. Phage display selection on
whole cells yields a peptide specific for melanocortin receptor 1. J Biol Chem. 1997; 272 (44) : 27943-8
90. Lowman HB. Phage display of peptide libraries on protein scaffolds. Methods Mol Biol. 1998; 87: 249-64
91. Klein J, Sato A. The HLA system. First of two parts. N Engl J Med. 2000 7; 343 (10) : 702-9
92. Klein J, Sato A. The HLA system. Second of two parts. N Engl J Med. 2000 14; 343 (11) : 782-6
93. Huang AY, Golumbek P, Ahmadzadeh M, et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science. 1994; 264 (5161) : 961-5
94. Pittet MJ, Zippelius A, Speiser DE, et al. Ex vivo IFN-gamma secretion by circulating CD8 T lymphocytes: implications of a novel approach for T cell monitoring in infectious and malignant diseases. J Immunol. 2001; 166 (12) : 7634-40.
95.张吉凤,台桂香,赵雷等.鼠与人MUC1分子同源性位点的分析.免疫学杂志,2003,19(2):83-85
96. Dai J, Allard WJ, Davis G, et al. Effect of desialylation on binding, affinity, and specificity of 56 monoclonal antibodies against MUC1 mucin. Tumour Biol. 1998; 19 (Suppl 1) : 100-10.
97. Young AC, Valadon P, Casadevall A, et al. The three-dimensional structures of a polysaccharide binding antibody to Cryptococcus neoformans and its complex with a peptide from a phage display library: implications for the identification of peptide mimotopes. J Mol Biol. 1997; 274 (4) : 622-34
98. Werdelin O, Meldal M, Jensen T. Processing of glycans on glycoprotein and glycopeptide antigens in antigen-presenting cells. Proc Natl Acad Sci U S A. 2002; 99 (15) : 9611-3.
99. Monzavi-Karbassi B, Cunto-Amesty G, Luo P, Shamloo S, Blaszcyk-Thurin M, Kieber-Emmons T. Immunization with a carbohydrate mimicking peptide augments tumor-specific cellular responses. Int Immunol. 2001;13(ll):136I-71.
100. Wang HY, Fu T, Wang G, Zeng G, et al. Induction of CD4(+) T cell-dependent antitumor immunity by TAT-mediated tumor antigen delivery into dendritic cells. J Clin Invest. 2002 Jun;109(11):1463-70.
101. Eguchi A, Akuta T, Okuyama H, et al. Protein transduction domain of HIV-1 Tat protein promotes efficient delivery of DNA into mammalian cells. J Biol Chem. 2001;276(28):26204-10
102. Spicer AP, Parry G, Patton S, et al. Molecular cloning and analysis of the mouse homologue of the tumor-associated mucin, MUC1, reveals conservation of potential O-glycosylation sites, transmembrane, and cytoplasmic domains and a loss of minisatellite-like polymorphism. J Biol Chem. 1991;266(23): 15099-109.
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