跳到主要內容

臺灣博碩士論文加值系統

(3.235.120.150) 您好!臺灣時間:2021/08/03 05:50
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:陳貞如
研究生(外文):Chen,Chen-Ju
論文名稱:EBV-del-LMP1腫瘤對趨化激素生成及免疫活化之影響
論文名稱(外文):The enhanced production of chemokines and immune down-modulation by the formation of solid tumor expressing EBV-del-LMP1
指導教授:周開平
指導教授(外文):Kai-ping Chow
學位類別:碩士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:英文
論文頁數:45
中文關鍵詞:單顆分離免疫力放射線測定法細胞株
外文關鍵詞:EBVN-LMP1inflammationtumor masschemokinetumorigenesis
相關次數:
  • 被引用被引用:0
  • 點閱點閱:140
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
許多文獻指出發炎反應與EB病毒相關的疾病及腫瘤之間有密切的關聯。 過去,本實驗室利用EBV致癌基因latent membrane protein-1 (LMP1) 引起的癌化特性建立了一個小鼠模式。本論文以此模式探討是否LMP1與發炎反應相關細胞激素之產生有關。藉由酵素免疫測定法 (ELISA) 和流式細胞多重訊號分析套組 (cytometric bead array; CBA) 分析來自表現LMP1的細胞株、腫瘤單顆分離細胞、及腫瘤團塊培養之上清液,得到如下幾項有趣的結果。相較於無LMP1表現之細胞株,LMP1的表現使細胞在抑制Th1的-Monocyte chemoattractant protein-1 (MCP-1) 的分泌上,有很大的增量表現。雖然LMP1表現細胞株本身並不分泌IL-1,IL-6,和TNF-α,但是若以腫瘤團塊或腫瘤單顆分離細胞的形式存在下,會增加這些細胞激素的分泌。此外,Macrophage inflammatory protein-2 (MIP-2) 的大量釋放於以腫瘤團塊、腫瘤單顆分離細胞形式培養的上清液中,也與LMP-1的存在有關。這些數據顯示LMP1可主動引起癌化過程中之發炎微環境。在此之前,本實驗室以放射線處理腫瘤單顆分離細胞作為腫瘤疫苗,接種於小鼠側背,數天後,於小鼠另一側背部移植腫瘤團塊,以測試疫苗的效果,結果發現,能成功引起抗腫瘤之免疫反應。而本論文更進一步發現若腫瘤團塊移植於接種疫苗同側,會大大影響疫苗的保護效果,於是測定在團塊附近的淋巴結細胞激素分泌的情形。結果發現大量MCP-1,IL-18 (促進Th2),和IL-10的分泌。相較於能夠引發對抗腫瘤的對照組,團塊附近的淋巴結IFN-γ的表現相形呈現低濃度的狀態。據此,我們發現LMP1致癌基因的表現與許多形成腫塊過程中的發炎相關激素生成有關。此外,對於已接種腫瘤疫苗之小鼠,腫瘤團塊結構能進一步造成腫瘤鄰近之淋巴結形成傾向Th2的微環境,至終有利於腫瘤在免疫力完好的宿主中生存下來。
Epstein-Barr virus (EBV)-encoded oncogene latent membrane protein-1 (LMP1) has been considered as one of the important cofactors in the tumorigenesis of nasopharyngeal carcinoma (NPC). As NPC generally displays a highly infiltrating nature, whether LMP1 induces the inflammation has been investigated in an N-LMP1 mouse tumor model established in this laboratory. The cytokine pattern in the culture supernatants derived from LMP1 transfectants, tumor single cells (TSC), and tumor blocks was analyzed by ELISA and cytometric bead array (CBA) to compare with that of the vector-alone control cells. A great release of monocyte chemoattractant protein-1 (MCP-1) was found to be dependent on the presence of LMP1. In addition, although IL-1α, IL-6 and TNF-α were not secreted by LMP1 transfectants, they were much produced in the TSC and/or tumor block supernatants. Furthermore, macrophage inflammatory protein-1 (MIP-2) in TSC and tumor blocks is additionally activated in a LMP1-dependent manner. The results indicate that LMP1 actively induces an inflammatory niche during tumorigenesis. Previously, we have demonstrated TSC vaccine can raise an effective anti-tumor immunity by complete host protection after grafting a tumor block counterlaterally to the vaccination site. However, when tumor block was implanted to the proximate site, the tumor incidence was significantly increased. In comparison to different forms of tumor challenge, the immune subversion was mainly due to the tumor texture. The cytokine pattern in the draining lymph nodes was further explored. A mast production of MCP-1, IL-18 (Th2-promoting) and IL-10 were seen. In conclusion, our data suggest that LMP1 involves in multiple levels of inflammatory cytokine induction along the tumor establishment, and the formation of tumor mass structure is a critical step in the generation of a Th2-prone microenvironment in draining lymph node to favor the tumor survival in the immunocompetent host.
指導教授推薦書……………………………………………………………………..
口試委員會審定書…………………………………………………………………..
授權書………………………………………………………………………………..
誌謝…………………………………………………………………………………..
中文摘要…………………………………………………………………….……….
Abstract ………..…………………………………………………………………….
Introduction………………………………………………………………………….1
Material and Methods……………………………………………………………….4
Results……………………………………………………………………………….9
Discussion………………………………………………………………………….17
Reference………………………………………………………………………......22
Tables and Figures…………………………………………………………………28
1.Balkwill, F., and A. Mantovani. 2001. Inflammation and cancer: back to Virchow? Lancet 357:539-545.
2.Coussens, L.M., and Z. Werb. 2002. Inflammation and cancer. Nature 420:860-867.
3.Cohen, J.I. 2000. Epstein-Barr virus infection. N Engl J Med 343:481-492.
4.Li, H.P., and Y.S. Chang. 2003. Epstein-Barr virus latent membrane protein 1: structure
and functions. J Biomed Sci 10:490-504.
5.Sandvej, K., S.C. Peh, B.S. Andresen, and G. Pallesen. 1994. Identification of potential
hot spots in the carboxy-terminal part of the Epstein-Barr virus (EBV) BNLF-1 gene in
both malignant and benign EBV-associated diseases: high frequency of a 30-bp deletion
in Malaysian and Danish peripheral T-cell lymphomas. Blood 84:4053-4060.
6.Knecht, H., E. Bachmann, P. Brousset, S. Rothenberger, H. Einsele, V.S. Lestou, G.
Delsol, F. Bachmann, P.F. Ambros, and B.F. Odermatt. 1995. Mutational hot spots
within the carboxy terminal region of the LMP1 oncogene of Epstein-Barr virus are
frequent in lymphoproliferative disorders. Oncogene 10:523-528.
7.Hu, L.F., E.R. Zabarovsky, F. Chen, S.L. Cao, I. Ernberg, G. Klein, and G. Winberg.
1991. Isolation and sequencing of the Epstein-Barr virus BNLF-1 gene (LMP1) from a
Chinese nasopharyngeal carcinoma. J Gen Virol 72 ( Pt 10):2399-2409.
8.Chen, M.L., C.N. Tsai, C.L. Liang, C.H. Shu, C.R. Huang, D. Sulitzeanu, S.T. Liu, and
Y.S. Chang. 1992. Cloning and characterization of the latent membrane protein (LMP) of
a specific Epstein-Barr virus variant derived from the nasopharyngeal carcinoma in the
Taiwanese population. Oncogene 7:2131-2140.
9.Hu, L.F., F. Chen, X. Zheng, I. Ernberg, S.L. Cao, B. Christensson, G. Klein, and G.
Winberg. 1993. Clonability and tumorigenicity of human epithelial cells expressing the
EBV encoded membrane protein LMP1. Oncogene 8:1575-1583.
10.Zheng, X., F. Yuan, L. Hu, F. Chen, G. Klein, and B. Christensson. 1994. Effect of
beta-lymphocyte- and NPC-derived EBV-LMP1 gene expression on in vitro growth and
differentiation of human epithelial cells. Int J Cancer 57:747-753.
11.Agathanggelou, A., G. Niedobitek, R. Chen, J. Nicholls, W. Yin, and L.S. Young.
1995. Expression of immune regulatory molecules in Epstein-Barr virus-associated
nasopharyngeal carcinomas with prominent lymphoid stroma. Evidence for a functional
interaction between epithelial tumor cells and infiltrating lymphoid cells. Am J Pathol
147:1152-1160.
12.Herait, P., G. Ganem, M. Lipinski, C. Carlu, C. Micheau, G. Schwaab, G. De-The, and
T. Tursz. 1987. Lymphocyte subsets in tumour of patients with undifferentiated
nasopharyngeal carcinoma: presence of lymphocytes with the phenotype of activated T
cells. Br J Cancer 55:135-139.
13.Ferradini, L., S. Miescher, M. Stoeck, P. Busson, C. Barras, N. Cerf-Bensussan, M.
Lipinski, V. von Fliedner, and T. Tursz. 1991. Cytotoxic potential despite impaired
activation pathways in T lymphocytes infiltrating nasopharyngeal carcinoma. Int J
Cancer 47:362-370.
14.Tang, K.F., S.H. Chan, K.S. Loh, S.M. Chong, D. Wang, K.H. Yeoh, and H. Hu. 1999.Increased production of interferon-gamma by tumour infiltrating T lymphocytes in nasopharyngeal carcinoma: indicative of an activated status. Cancer Lett 140:93-98.
15.Dvorak, H.F. 2003. Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. Am J Pathol 162:1747-1757.
16.Yoshizaki, T., T. Horikawa, R. Qing-Chun, N. Wakisaka, H. Takeshita, T.S. Sheen, S.Y. Lee, H. Sato, and M. Furukawa. 2001. Induction of interleukin-8 by Epstein-Barr
virus latent membrane protein-1 and its correlation to angiogenesis in nasopharyngeal
carcinoma. Clin Cancer Res 7:1946-1951.
17.Tang, K.F., S.Y. Tan, S.H. Chan, S.M. Chong, K.S. Loh, L.K. Tan, and H. Hu. 2001.
A distinct expression of CC chemokines by macrophages in nasopharyngeal carcinoma:
implication for the intense tumor infiltration by T lymphocytes and macrophages. Hum
Pathol 32:42-49.
18.Chang, Y.S., I.J. Su, P.J. Chung, C.H. Shu, C.K. Ng, S.J. Wu, and S.T. Liu. 1995.
Detection of an Epstein-Barr-virus variant in T-cell-lymphoma tissues identical to the
distinct strain observed in nasopharyngeal carcinoma in the Taiwanese population. Int J
Cancer 62:673-677.
19.Teichmann, M., B. Meyer, A. Beck, and G. Niedobitek. 2005. Expression of the
interferon-inducible chemokine IP-10 (CXCL10), a chemokine with proposed
anti-neoplastic functions, in Hodgkin lymphoma and nasopharyngeal carcinoma. J Pathol
206:68-75.
20.Omata, N., M. Yasutomi, A. Yamada, H. Iwasaki, M. Mayumi, and Y. Ohshima. 2002. Monocyte chemoattractant protein-1 selectively inhibits the acquisition of CD40 ligand-dependent IL-12-producing capacity of monocyte-derived dendritic cells and modulates Th1 immune response. J Immunol 169:4861-4866.
21.Stoll, S., H. Jonuleit, E. Schmitt, G. Muller, H. Yamauchi, M. Kurimoto, J. Knop, and A.H. Enk. 1998. Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development. Eur J Immunol 28:3231-3239.
22.Nakanishi, K., T. Yoshimoto, H. Tsutsui, and H. Okamura. 2001. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 19:423-474.
23.Conti, I., and B.J. Rollins. 2004. CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol 14:149-154.
24.Karpus, W.J., N.W. Lukacs, K.J. Kennedy, W.S. Smith, S.D. Hurst, and T.A. Barrett. 1997. Differential CC chemokine-induced enhancement of T helper cell cytokine production. J Immunol 158:4129-4136.
25.Pathmanathan, R., U. Prasad, R. Sadler, K. Flynn, and N. Raab-Traub. 1995. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 333:693-698.
26.Belperio, J.A., M.P. Keane, D.A. Arenberg, C.L. Addison, J.E. Ehlert, M.D. Burdick, and R.M. Strieter. 2000. CXC chemokines in angiogenesis. J Leukoc Biol 68:1-8.
27.Tessier, P.A., P.H. Naccache, I. Clark-Lewis, R.P. Gladue, K.S. Neote, and S.R. McColl. 1997. Chemokine networks in vivo: involvement of C-X-C and C-C chemokines in neutrophil extravasation in vivo in response to TNF-alpha. J Immunol 159:3595-3602.
28.Faunce, D.E., K.H. Sonoda, and J. Stein-Streilein. 2001. MIP-2 recruits NKT cells to the spleen during tolerance induction. J Immunol 166:313-321.
29.Bashford, E., J. Murray, and M. Haaland. 1908. Resistance and susceptibility to inoculated cancer. In Third Scientific Report on the Investigations of the Imperial Cancer Research Fund. E. Bashford, editor. Taylor & Francis, London, England. 359?97.
30.Ehrlich, P. 1906. Collected Studies on Immunity.
31.North, R.J., and I. Bursuker. 1984. Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2- suppressor T cells down-regulate the generation of Ly-1-2+ effector T cells. J Exp Med 159:1295-1311.
32.DiGiacomo, A., and R.J. North. 1986. T cell suppressors of antitumor immunity. The production of Ly-1-,2+ suppressors of delayed sensitivity precedes the production of suppressors of protective immunity. J Exp Med 164:1179-1192.
33.Toney, L.M., G. Cattoretti, J.A. Graf, T. Merghoub, P.P. Pandolfi, R. Dalla-Favera, B.H. Ye, and A.L. Dent. 2000. BCL-6 regulates chemokine gene transcription in macrophages. Nat Immunol 1:214-220.
34.Lu, B., B.J. Rutledge, L. Gu, J. Fiorillo, N.W. Lukacs, S.L. Kunkel, R. North, C. Gerard, and B.J. Rollins. 1998. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 187:601-608.
35.Gu, L., S. Tseng, R.M. Horner, C. Tam, M. Loda, and B.J. Rollins. 2000. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404:407-411.
36.Peters, W., H.M. Scott, H.F. Chambers, J.L. Flynn, I.F. Charo, and J.D. Ernst. 2001. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 98:7958-7963.
37.Peters, W., M. Dupuis, and I.F. Charo. 2000. A mechanism for the impaired IFN-gamma production in C-C chemokine receptor 2 (CCR2) knockout mice: role of CCR2 in linking the innate and adaptive immune responses. J Immunol 165:7072-7077.
38.Sato, N., S.K. Ahuja, M. Quinones, V. Kostecki, R.L. Reddick, P.C. Melby, W.A. Kuziel, and S.S. Ahuja. 2000. CC chemokine receptor (CCR)2 is required for langerhans cell migration and localization of T helper cell type 1 (Th1)-inducing dendritic cells. Absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptible state dominated by Th2 cytokines, b cell outgrowth, and sustained neutrophilic inflammation. J Exp Med 192:205-218.
39.Steinbrink, K., M. Wolfl, H. Jonuleit, J. Knop, and A.H. Enk. 1997. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159:4772-4780.
40.Marshall, N.A., M.A. Vickers, and R.N. Barker. 2003. Regulatory T cells secreting IL-10 dominate the immune response to EBV latent membrane protein 1. J Immunol 170:6183-6189.
41.Arvanitakis, L., N. Yaseen, and S. Sharma. 1995. Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. J Immunol 155:1047-1056.
42.Prokova, V., G. Mosialos, and D. Kardassis. 2002. Inhibition of transforming growth factor beta signaling and Smad-dependent activation of transcription by the Latent Membrane Protein 1 of Epstein-Barr virus. J Biol Chem 277:9342-9350.
43.Curiel, T.J., G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J.R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M.L. Disis, K.L. Knutson, L. Chen, and W. Zou. 2004. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942-949.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top