臺灣博碩士論文加值系統

腫瘤細胞具有逃避免疫系統監測之機制，因而在體內不停增生，使宿主生理功用失常，加上惡性腫瘤細胞的轉移最終造成嚴重後果。腫瘤細胞逃避免疫系統監測機制中主要包括(1)使免疫系統失去辨識能力。最常見的是主要組織相容複合物 (Major histocopatibility complex, MHC)不表現或表現量極低，(2)免疫系統毒殺腫瘤細胞能力下降。抑制免疫細胞之毒殺作用包括T細胞及NK細胞，及 (3)分泌抑制性分子，抑制免疫細胞的作用。
因為犬傳染性花柳性腫瘤(canine transmissible venereal tumor, CTVT)生長期時，TGF-β除了抑制IFN-γ誘導MHC作用，並抑制(tumor infiltrating lymphocyte, TIL)的毒殺能力，造成CTVT在宿主體內快速生長。但實驗接種CTVT於犬隻背部皮下後會自然地進入消退期(R期)。造成消退的主因來自R期時TIL分泌大量的IL-6，拮抗TGF-β抑制IFN-γ之作用，使IFN-γ能誘導CTVT的MHC表現，使T細胞活化。另外IL-6也拮抗TGF-β抑制NK細胞的毒殺能力，腫瘤因此進入R期。
本實驗乃針對CTVT之特性，嘗試以IL-6導入基因解除TGF-β對免疫系統抑制能力，使CTVT細胞之MHC分子表現量上升，更進一步導入IL-15基因活化免疫系統，達到成功治療腫瘤之目的。因此構築IL-6及IL-15基因的質體，用腫瘤內電衝方式治療CTVT，並研究此基因治療的效果與抗腫瘤機制。實驗結果證明合併使用IL-6與IL-15不但能顯著的延緩CTVT的生長更可以成功使腫瘤消退。在複合式療法下，腫瘤中IL-6與IL-15的濃度增加，腫瘤細胞的MHC表現量上昇，MHCⅠ 由治療前5.91%至治療後第四週已上昇至34%；MHCⅡ 由治療前8.86%至治療後第四週已上昇至25.86%。同時發現腫瘤內TIL浸潤程度增加，其中CD8+T細胞佔TIL之百分比有顯著上昇的情形，由5.84%上昇至21.63%。而在腫瘤細胞產生細胞素之能力方面，經治療後，IL-8與TNF-α表現量顯著性上昇，但功用仍不明朗，但CTVT分泌TGF-β的能力則不會因治療而造成影響。而且此療法能有效提升NK細胞與CTL的毒殺能力，然而B細胞受CTVT殺害而數量低落之狀況並未能改善。以上這些結果顯示使用腫瘤內電衝，進行IL-6與IL-15基因治療，在實驗犬模式，可成功破壞腫瘤逃避免疫系統的作用並提昇免疫反應，達到成功治療腫瘤之目的。本研究結果所使用之策略包括：一方面使用IL-6提高MHC的表現，一方面以IL-15強化NK細胞的作用，可做為未來對腫瘤治療上的一個新選擇。

Malignant cells escape from the surveillance of immune system and proliferate unrestrictedly. They cause severe alternations on host physiological activities.
Malignant cells can metastasize and create further disturbances on normal functions of tissues and organs. There are three major mechanisms for tumor cell to escape: (1)Loss of recognition of foreign antigens. Tumor cells do not express MHCⅠmolecule to escape T lymphocytes recongition. (2) Decrease of cytotoxicity. Decrease the cytotoxiciity of T cells and NK cells (3)Inhibition of immune system. Tumor cells or stromal cells produce some inhibiting factors to suppress the function of immune stystem.
During progression, canine transmissible venereal tumor (CTVT) secretes TGF-β to inhibit the IFN-γ induction of MHC molecules and the cytotoxicity of tumor infiltrating lymphocytes (TIL). In experimentally transplanted CTVT, it exhibits a spontaneous regression (R phase). This is due to the fact that TIL secret high concentration of IL-6 from TIL in R phase, which antagonizes the activity of tumor-derived TGF-β. After the release of TGF-β inhibition, IFN-γ can restore the MHC expression activity and T cells are activated. IL-6 also restore the cytotoxicity of NK cells. That is once inhibited by TGF-β.
This research first used IL-6 gene delivery intratumorly through electroporation to antagonize TGF-β activity to promote MHC expression and then by additional IL-15 gene delivery to activate T and NK cells activities. This combinatize successfully treat this tumor in dogs. Besides, we have studied the mechanism of the combined immunogene. The combined treatment of IL-6 and IL-15 inhibited the growth or eiminated CTVT. The surface expression of MHCⅠmolecules on CTVT cells was significantly increased after gene therapy from 5.9% to 34% and MHCⅡ from 8.86% to 25.86% . This gene therapy induced more infiltrating lymphocytes from in the tumors with significant higher percentage of CD8+ T cell from 5.84% to 21.64%. This treatment also changed the cytokine profile of CTVT in favor of immune response. The mRNA levels of IL-1β, IL-8 and TNF-α were increased. But, there were no difference in TGF-β secreting activity of CTVT cells. NK cells and CTL cytotoxicity were also greatly enhanced. In conclusion, our results demonstrated that intratumoral electroporation-mediated IL-6 and IL-15 gene therapy for canine transmissible venereal tumor in the canine model efficiently tumor escape mechanism and also intensified the host immune responses. This strategy to promote MHC expression and enhance the responses on NK and other immune cells could be additional choice for cancer therapy.

誌謝••••••••••••••••••••••••••••••••Ⅱ
中文摘要••••••••••••••••••••••••••••••Ⅳ
英文摘要••••••••••••••••••••••••••••••Ⅵ
目錄••••••••••••••••••••••••••••••••Ⅷ
圖次•••••••••••••••••••••••••••••••ⅩⅢ
表次•••••••••••••••••••••••••••••••ⅩⅤ
縮寫符號•••••••••••••••••••••••••••••ⅩⅥ
第一章 緒言•••••••••••• •••••••••••••••••1
第二章 文獻探討••••••••••••••••••••• ••••••3
第一節 介白素-6(Interleukin-6, IL-6)•••••4
一、IL-6分子•••••••••••••••••••••••5
二、IL-6的來源••••••••••••••••••••••6
三、IL-6的接受器•••••••••••••••••••••6
四、IL-6的功能••••••••••••••••••••••7
五、IL-6在腫瘤中扮演的角色••••••••••••••••7
第二節介白素-15 (Interleukin-15, IL-15) ••• ••• ••••••10
一、IL-15分子••••••••••••••••••••••10
二、IL-15的來源•••••••••••••••••••••10
三、IL-15的接受器••••••••••••••••••••10
四、IL-15的功能•••••••••••••••••••••12
1.IL-15對NK細胞的功能 •••••••••••••••12
2.對T細胞的功能 ••• •••••••••••••••13
3.對B細胞的功能 ••••• •••••••••••••13
4.對APC的功能 •••••••••••••••••••13
5.對neutrophil、eosinophil的功能••••••••••••14
五、IL-15在腫瘤基因治療上扮演的角色 •••• •••• ••15
第三節犬傳染性花柳性腫瘤•••• •••••••••••••17
一、臨床特性•••••••• ••••••••••••••17
二、病理特徵••• •••••••••••••••••••18
三、細胞特性•••• ••••••••••••••••••18
四、遺傳物質特性•••••••• ••••••••••••18
五、實驗接種後對免疫系統的影響••••••• ••••••19
第四節活體基因電衝•••••••••••••• ••••••22
一、活體基因電衝之原理與作用機制•••• ••••••••22
二、基因電衝的影響因子•••••••• •••••••••24
第三章 研究策略 ••••••••••••••••••••••••••27
第四章 材料與方法•••••••••••••• • ••••••••••30
第一節人類IL-6及IL-15基因之取得與合成 ••••••••••30
一、引子設計• •••• •••••••••••••••••33
二、聚合脢連鎖反應 (Polymerase chain reaction, PCR) •••••34
1. IL-6•••••••••••••••••••••••34
2. 人類IL-2 signal peptide/IL-15 mature peptide基因••••34
第二節IL-6及IL-15表現質體之構築••••••••••••••35
一、基因選殖與質體轉形（Transformation）••••••••••35
二、質體DNA之小量分離法••••••••••••••••36
三、限制脢脢切作用••• ••••••••••••••••37
四、質體DNA之定序與基因序列比對••••••••••••37
第三節 質體DNA於哺乳類細胞株之轉染••••••••••••39
一、Seeding cells•••••••••••••••••••••39
二、質體轉染•••••••• ••••••••••••••39
第四節IL-6及IL-15之功能性測試•••••••••••••••41
一、細胞培養•••• ••••••• •••••••••••41
1.TF-1細胞株 ••••••••••••••••••••41
2.TF-1細胞株 ••••••••••••••••••••41
二、CellTiter 96® AQueous One Solution細胞分裂能力試驗•••41
1.使用IL-6 dependent cell line進行功能性測試 • •••••41
2.IL-15質體轉染產物之測試••••••••••••••42
三、BALB/3T3上清液IL-6及IL-15之ELISA試驗•••••••43
1.IL-6••••••••••••••••••••••••43
2.IL-15 •••• •• ••• ••• ••••• •••••43
第五節大量質體純化製備••••••••• • ••••••••45
第六節CTVT的接種••••• •••••• • ••••••••47
一、實驗動物•••••••••• ••••••• •••••47
二、CTVT的分離與接種••••• ••••••• • ••••47
第七節 電衝轉染IL-6和IL-15質體治療CTVT••• • •••••48
一、質體DNA的腫瘤注射與電衝• •••••• • •••••48
二、腫瘤體積的測量• ••••••••••••• •••••48
第八節IL-6和IL-15基因治療後樣本之採集與檢測••••••••49
一、基因治療後血清的取得•••••• ••• •••••••49
二、血清IL-6及IL-15之ELISA試驗 ••••••••••••49
三、收集治療後之腫瘤樣品 ••••••••••••••••49
四、腫瘤組織學分析 •••••••••••••••••••50
五、IL-6與IL-15質體在腫瘤內表現的狀況••••••••••50
六、血清IL-6及IL-15之ELISA試驗••••••••••••50
第九節IL-6和IL-15對CTVT的影響••••••••••••••51
一、CTVT細胞表面MHC之表現••••••••••••••51
二、TIL population••••••••••••••• •••••51
三、CTVT細胞cDNA的製作與real time RT-PCR•••••••52
1.RNA之純化•••••• •••••• ••••••••52
2.反轉錄聚合酶連鎖反應 ( Reverse transcription - Polymerase chain reaction, RT-PCR ) •••••••• •••••••52
3.real-time RT-PCR••••••• •••••• •••••53
第十節IL-6和IL-15對宿主免疫系統之影響•••••••••••56
一、犬週邊血液單核球 ( Peripheral blood mononuclear cell, PBMC ) 之純化•56
二、犬週邊血液淋巴球 ( Peripheral blood lymphocytes, PBL ) 之純化••••56
三、PBL中NK細胞毒殺能力測驗••• ••••••••••56
四、CTL毒殺能力測驗•••••••• ••••••••••58
五、ELISPOT毒殺能力測驗•••••• ••••••••••61
第十一節IL-6和IL-15基因電衝治療之毒性測試••••••••••62
一、實驗犬之存活率•••••••• • ••••••••••62
二、實驗犬之臨床症狀••••••• ••• ••••••••62
三、血液生化學檢查••••• •••••• ••••••••62
第十二節實驗犬處理••••••• •••••• ••••••••63
第十三節統計分析••••••• •••••••• •••••••63
第五章 結果••••••••••••••• •••• •• •••••64
第一節 人類IL-6及IL-15質體轉殖••••• ••••• ••••64
一、 以聚合脢連鎖反應確認IL-6和IL-15之表現•• •••••64
二、 IL-6和IL-15質體DNA之定序與基因序列比對••••••67
第二節IL-6及IL-15之功能性測試•••••••••••••••71
一、IL-6及IL-15之ELISA試驗•••••••••••••••72
二、轉染IL-6後Balb/3T3上清液對TF-1生長之影響••••••73
三、轉染IL-15之上清液對HT-2生長之影響•••• •••••74
第三節IL-6和IL-15基因治療對CTVT生長之抑制••••••••75
第四節IL-6和IL-15基因治療前對CTVT細胞表面MHC之影響••79
第五節IL-6與IL-15合併治療後對TIL之影響與次族群的變化•••81
第六節腫瘤與血清中IL-6及IL-15濃度之消長 ••• ••••••84
第七節IL-6和IL-15基因治療前後CTVT cytokine profile之變化••87
第八節IL-6和IL-15基因治療對犬NK細胞毒殺能力之影響••••89
第九節IL-6和IL-15基因治療對犬毒殺T淋巴球毒殺能力之實驗••91
一、CTL實驗••••••••• •• •••••••••••91
二、ELISPOT（Enzyme-linked immunospot assay）•••••••93
第十節IL-6和IL-15基因治療對犬周邊B細胞之影響•••••••94
第十一節IL-6和IL-15基因電衝治療之毒性測試••••••••••96
第六章 討論••••••••• •••••••••••••••••••99
第七章 參考文獻••••••••••••••••••••••••••105

1.Kishimoto, T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther, 8 Suppl 2: S2, 2006.
2.Knupfer, H. and Preiss, R. Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat, 2006.
3.Chen, R. H., Chang, M. C., Su, Y. H., Tsai, Y. T., and Kuo, M. L. Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem, 274: 23013-23019, 1999.
4.Kitamura, H., Kamon, H., Sawa, S., Park, S. J., Katunuma, N., Ishihara, K., Murakami, M., and Hirano, T. IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells. Immunity, 23: 491-502, 2005.
5.Cao, X., Chen, G., He, L., Zhang, W., Yu, Y., and Wang, J. Involvement of MHC class I molecule and ICAM-1 in the enhancement of adhesion and cytotoxic susceptibility to immune effector cells of tumor cells transfected with the interleukin (IL)-2, IL-4 or IL-6 gene. J Cancer Res Clin Oncol, 123: 602-608, 1997.
6.Markine-Goriaynoff, D., Nguyen, T. D., Bigaignon, G., Van Snick, J., and Coutelier, J. P. Distinct requirements for IL-6 in polyclonal and specific Ig production induced by microorganisms. Int Immunol, 13: 1185-1192, 2001.
7.van Kooten, C., Rensink, I., Aarden, L., and van Oers, R. Effect of IL-4 and IL-6 on the proliferation and differentiation of B-chronic lymphocytic leukemia cells. Leukemia, 7: 618-624, 1993.
8.Rincon, M., Anguita, J., Nakamura, T., Fikrig, E., and Flavell, R. A. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J Exp Med, 185: 461-469, 1997.
9.Vredevoe, D. L., Widawski, M., Fonarow, G. C., Hamilton, M., Martinez-Maza, O., and Gage, J. R. Interleukin-6 (IL-6) expression and natural killer (NK) cell dysfunction and anergy in heart failure. Am J Cardiol, 93: 1007-1011, 2004.
10.Gaforio, J. J., Ortega, E., Algarra, I., Serrano, M. J., and Alvarez de Cienfuegos, G. NK cells mediate increase of phagocytic activity but not of proinflammatory cytokine (interleukin-6 [IL-6], tumor necrosis factor alpha, and IL-12) production elicited in splenic macrophages by tilorone treatment of mice during acute systemic candidiasis. Clin Diagn Lab Immunol, 9: 1282-1294, 2002.
11.Cabillic, F., Bouet-Toussaint, F., Toutirais, O., Rioux-Leclercq, N., Fergelot, P., de la Pintiere, C. T., Genetet, N., Patard, J. J., and Catros-Quemener, V. Interleukin-6 and vascular endothelial growth factor release by renal cell carcinoma cells impedes lymphocyte-dendritic cell cross-talk. Clin Exp Immunol, 146: 518-523, 2006.
12.Yajima, T., Nishimura, H., Sad, S., Shen, H., Kuwano, H., and Yoshikai, Y. A novel role of IL-15 in early activation of memory CD8+ CTL after reinfection. J Immunol, 174: 3590-3597, 2005.
13.Kanai, T., Thomas, E. K., Yasutomi, Y., and Letvin, N. L. IL-15 stimulates the expansion of AIDS virus-specific CTL. J Immunol, 157: 3681-3687, 1996.
14.Klebanoff, C. A., Finkelstein, S. E., Surman, D. R., Lichtman, M. K., Gattinoni, L., Theoret, M. R., Grewal, N., Spiess, P. J., Antony, P. A., Palmer, D. C., Tagaya, Y., Rosenberg, S. A., Waldmann, T. A., and Restifo, N. P. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci U S A, 101: 1969-1974, 2004.
15.Sechler, J. M., Barlic, J., Grivel, J. C., and Murphy, P. M. IL-15 alters expression and function of the chemokine receptor CX3CR1 in human NK cells. Cell Immunol, 230: 99-108, 2004.
16.Ashkar, A. A., Black, G. P., Wei, Q., He, H., Liang, L., Head, J. R., and Croy, B. A. Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy. J Immunol, 171: 2937-2944, 2003.
17.Fawaz, L. M., Sharif-Askari, E., and Menezes, J. Up-regulation of NK cytotoxic activity via IL-15 induction by different viruses: a comparative study. J Immunol, 163: 4473-4480, 1999.
18.Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol, 6: 595-601, 2006.
19.Pardali, K. and Moustakas, A. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta, 1775: 21-62, 2007.
20.Saunier, E. F. and Akhurst, R. J. TGF beta inhibition for cancer therapy. Curr Cancer Drug Targets, 6: 565-578, 2006.
21.Hsiao, Y. W., Liao, K. W., Hung, S. W., and Chu, R. M. Tumor-infiltrating lymphocyte secretion of IL-6 antagonizes tumor-derived TGF-beta 1 and restores the lymphokine-activated killing activity. J Immunol, 172: 1508-1514, 2004.
22.Hirano, T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol, 16: 249-284, 1998.
23.Scheller, J. and Rose-John, S. Interleukin-6 and its receptor: from bench to bedside. Med Microbiol Immunol (Berl), 195: 173-183, 2006.
24.Naka, T., Nishimoto, N., and Kishimoto, T. The paradigm of IL-6: from basic science to medicine. Arthritis Res, 4 Suppl 3: S233-242, 2002.
25.Rose-John, S. and Neurath, M. F. IL-6 trans-signaling: the heat is on. Immunity, 20: 2-4, 2004.
26.Scheller, J., Ohnesorge, N., and Rose-John, S. Interleukin-6 trans-signalling in chronic inflammation and cancer. Scand J Immunol, 63: 321-329, 2006.
27.Kishimoto, T., Akira, S., Narazaki, M., and Taga, T. Interleukin-6 family of cytokines and gp130. Blood, 86: 1243-1254, 1995.
28.Smith, P. C., Hobisch, A., Lin, D. L., Culig, Z., and Keller, E. T. Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev, 12: 33-40, 2001.
29.Becker, C., Fantini, M. C., Wirtz, S., Nikolaev, A., Lehr, H. A., Galle, P. R., Rose-John, S., and Neurath, M. F. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle, 4: 217-220, 2005.
30.Chiu, J. J., Sgagias, M. K., and Cowan, K. H. Interleukin 6 acts as a paracrine growth factor in human mammary carcinoma cell lines. Clin Cancer Res, 2: 215-221, 1996.
31.Franchimont, N., Wertz, S., and Malaise, M. Interleukin-6: An osteotropic factor influencing bone formation? Bone, 37: 601-606, 2005.
32.White, L., Krishnan, S., Strbo, N., Liu, H., Kolber, M. A., Lichtenheld, M. G., Pahwa, R., and Pahwa, S. Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation and proliferation in CD8 T cells of patients infected with Human Immunodeficiency Virus-1 (HIV). Blood, 2006.
33.Smolen, J. S. and Maini, R. N. Interleukin-6: a new therapeutic target. Arthritis Res Ther, 8 Suppl 2: S5, 2006.
34.Arnoult, D., Petit, F., Lelievre, J. D., Lecossier, D., Hance, A., Monceaux, V., Hurtrel, B., Ho Tsong Fang, R., Ameisen, J. C., and Estaquier, J. Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression. Cell Death Differ, 10: 1240-1252, 2003.
35.Nishimoto, N. Interleukin-6 in rheumatoid arthritis. Curr Opin Rheumatol, 18: 277-281, 2006.
36.Yokoyama, A. [Interleukin-6 (IL-6) /soluble IL-6 receptor]. Nippon Rinsho, 63 Suppl 8: 72-74, 2005.
37.Gamero, A. M., Young, H. A., and Wiltrout, R. H. Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer? Cancer Cell, 5: 111-112, 2004.
38.Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F., and Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J, 334 ( Pt 2): 297-314, 1998.
39.Diehl, S. and Rincon, M. The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol, 39: 531-536, 2002.
40.Emilie, D., Leger-Ravet, M. B., Devergne, O., Raphael, M., Peuchmaur, M., Coumbaras, J., Crevon, M. C., and Galanaud, P. Intratumoral production of IL-6 in B cell chronic lymphocytic leukemia and B lymphomas. Leuk Lymphoma, 11: 411-417, 1993.
41.de la Barrera, S., Finiasz, D. M., Fink, S., Valdez, R., Bottasso, O., Balina, L. M., and Sasiain, M. C. Differential development of CD4 and CD8 cytotoxic T cells (CTL) in PBMC across the leprosy spectrum; IL-6 with IFN-gamma or IL-2 generate CTL in multibacillary patients. Int J Lepr Other Mycobact Dis, 65: 45-55, 1997.
42.Hatabu, T., Matsumoto, Y., Kawazu, S., Nakamura, Y., Kamio, T., Lu, H. G., Chang, K. P., Hashiguchi, Y., Kano, S., Onodera, T., and Matsumoto, Y. The expression system of biologically active canine interleukin-8 in Leishmania promastigotes. Parasitol Int, 51: 63-71, 2002.
43.Ashizawa, T., Okada, R., Suzuki, Y., Takagi, M., Yamazaki, T., Sumi, T., Aoki, T., and Aoki, T. Study of interleukin-6 in the spread of colorectal cancer: the diagnostic significance of IL-6. Acta Med Okayama, 60: 325-330, 2006.
44.Nikiteas, N. I., Tzanakis, N., Gazouli, M., Rallis, G., Daniilidis, K., Theodoropoulos, G., Kostakis, A., and Peros, G. Serum IL-6, TNFalpha and CRP levels in Greek colorectal cancer patients: prognostic implications. World J Gastroenterol, 11: 1639-1643, 2005.
45.Fujimoto-Ouchi, K., Onuma, E., Shirane, M., Mori, K., and Tanaka, Y. Capecitabine improves cancer cachexia and normalizes IL-6 and PTHrP levels in mouse cancer cachexia models. Cancer Chemother Pharmacol, 2006.
46.Wang, Y., Yang, J., Gao, Y., Du, Y., Bao, L., Niu, W., and Yao, Z. Regulatory effect of e2, IL-6 and IL-8 on the growth of epithelial ovarian cancer cells. Cell Mol Immunol, 2: 365-372, 2005.
47.Hess, S., Smola, H., Sandaradura De Silva, U., Hadaschik, D., Kube, D., Baldus, S. E., Flucke, U., and Pfister, H. Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte chemoattractant protein-1 production. J Immunol, 165: 1939-1948, 2000.
48.Bauknecht, T., Randelzhofer, B., Schmitt, B., Ban, Z., and Hernando, J. J. Response to IL-6 of HPV-18 cervical carcinoma cell lines. Virology, 258: 344-354, 1999.
49.Kovalchuk, A. L., Kim, J. S., Park, S. S., Coleman, A. E., Ward, J. M., Morse, H. C., 3rd, Kishimoto, T., Potter, M., and Janz, S. IL-6 transgenic mouse model for extraosseous plasmacytoma. Proc Natl Acad Sci U S A, 99: 1509-1514, 2002.
50.Ashizawa, T., Okada, R., Suzuki, Y., Takagi, M., Yamazaki, T., Sumi, T., Aoki, T., Ohnuma, S., and Aoki, T. Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor. Gastric Cancer, 8: 124-131, 2005.
51.Alberti, L., Thomachot, M. C., Bachelot, T., Menetrier-Caux, C., Puisieux, I., and Blay, J. Y. IL-6 as an intracrine growth factor for renal carcinoma cell lines. Int J Cancer, 111: 653-661, 2004.
52.Waldmann, T. A. IL-15 in the life and death of lymphocytes: immunotherapeutic implications. Trends Mol Med, 9: 517-521, 2003.
53.Yang, J., Hagan, M. K., and Offermann, M. K. Induction of IL-6 gene expression in Kaposi''s sarcoma cells. J Immunol, 152: 943-955, 1994.
54.Spachacz, R., Kasprzak, A., Stefanska, K., Trejster, E., Seidel, J., and Zabel, M. Tissue expression of cytokines (IL-1alpha, IL-2, IL-6, IL-12, TNF-alpha) in B-cell lymphomas in children. Folia Morphol (Warsz), 62: 483-484, 2003.
55.Denizot, Y., Fixe, P., Liozon, E., Brigaudeau, C., and Praloran, V. Serum IL-6 concentrations in lymphomas. Br J Haematol, 90: 731-732, 1995.
56.Asgeirsson, K. S., Olafsdottir, K., Jonasson, J. G., and Ogmundsdottir, H. M. The effects of IL-6 on cell adhesion and e-cadherin expression in breast cancer. Cytokine, 10: 720-728, 1998.
57.Kawamura, C., Nakajima, S., Kuroki, T., and Monna, T. Two-dimensional analysis of production of IL-6 and TNF-alpha can predict the efficacy of IFN-alpha therapy. Hepatogastroenterology, 46: 2941-2945, 1999.
58.Catlett-Falcone, R., Landowski, T. H., Oshiro, M. M., Turkson, J., Levitzki, A., Savino, R., Ciliberto, G., Moscinski, L., Fernandez-Luna, J. L., Nunez, G., Dalton, W. S., and Jove, R. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity, 10: 105-115, 1999.
59.Gomez-Bougie, P., Bataille, R., and Amiot, M. The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. Eur J Immunol, 34: 3156-3164, 2004.
60.Arihiro, K., Oda, H., Kaneko, M., and Inai, K. Cytokines facilitate chemotactic motility of breast carcinoma cells. Breast Cancer, 7: 221-230, 2000.
61.Wang, Q., Horiatis, D., and Pinski, J. Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation. Int J Cancer, 111: 508-513, 2004.
62.Honma, S., Shimodaira, K., Shimizu, Y., Tsuchiya, N., Saito, H., Yanaihara, T., and Okai, T. The influence of inflammatory cytokines on estrogen production and cell proliferation in human breast cancer cells. Endocr J, 49: 371-377, 2002.
63.Tsuberi, B. and Naparstek, E. Modification of M1 cells by exogenous introduction of IL6 gene: a model for gene therapy of acute and chronic myeloid leukemia in mice. Leukemia, 9 Suppl 1: S93-97, 1995.
64.Budagian, V., Bulanova, E., Paus, R., and Bulfone-Paus, S. IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev, 17: 259-280, 2006.
65.Waldmann, T., Tagaya, Y., and Bamford, R. Interleukin-2, interleukin-15, and their receptors. Int Rev Immunol, 16: 205-226, 1998.
66.Krause, H., Jandrig, B., Wernicke, C., Bulfone-Paus, S., Pohl, T., and Diamantstein, T. Genomic structure and chromosomal localization of the human interleukin 15 gene (IL-15). Cytokine, 8: 667-674, 1996.
67.van Heel, D. A. Interleukin 15: its role in intestinal inflammation. Gut, 55: 444-445, 2006.
68.McInnes, I. B. and Gracie, J. A. Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol, 4: 392-397, 2004.
69.Fehniger, T. A., Cooper, M. A., and Caligiuri, M. A. Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev, 13: 169-183, 2002.
70.Schluns, K. S., Stoklasek, T., and Lefrancois, L. The roles of interleukin-15 receptor alpha: trans-presentation, receptor component, or both? Int J Biochem Cell Biol, 37: 1567-1571, 2005.
71.Waldmann, T. A. Targeting the interleukin-15/interleukin-15 receptor system in inflammatory autoimmune diseases. Arthritis Res Ther, 6: 174-177, 2004.
72.Bulanova, E., Budagian, V., Pohl, T., Krause, H., Durkop, H., Paus, R., and Bulfone-Paus, S. The IL-15R alpha chain signals through association with Syk in human B cells. J Immunol, 167: 6292-6302, 2001.
73.Kennedy, M. K., Glaccum, M., Brown, S. N., Butz, E. A., Viney, J. L., Embers, M., Matsuki, N., Charrier, K., Sedger, L., Willis, C. R., Brasel, K., Morrissey, P. J., Stocking, K., Schuh, J. C., Joyce, S., and Peschon, J. J. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med, 191: 771-780, 2000.
74.Roberts, A., Lee, L., and Schwarz, E. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol 167: 5527-5530, 2001.
75.Carson, W. and Caligiuri, M. A. Interleukin-15 as a potential regulator of the innate immune response. Braz J Med Biol Res, 31: 1-9, 1998.
76.Becknell, B. and Caligiuri, M. A. Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol, 86: 209-239, 2005.
77.Ohteki, T., Tada, H., Ishida, K., Sato, T., Maki, C., Yamada, T., Hamuro, J., and Koyasu, S. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J Exp Med, 203: 2329-2338, 2006.
78.Liu, G., Zhai, Q., Schaffner, D., Bradburne, C., Wu, A., Hayford, A., Popov, S., Grene, E., Bailey, C., and Alibek, K. IL-15 induces IFN-beta and iNOS gene expression, and antiviral activity of murine macrophage RAW 264.7 cells. Immunol Lett, 91: 171-178, 2004.
79.Neely, G. G., Robbins, S. M., Amankwah, E. K., Epelman, S., Wong, H., Spurrell, J. C., Jandu, K. K., Zhu, W., Fogg, D. K., Brown, C. B., and Mody, C. H. Lipopolysaccharide-stimulated or granulocyte-macrophage colony-stimulating factor-stimulated monocytes rapidly express biologically active IL-15 on their cell surface independent of new protein synthesis. J Immunol, 167: 5011-5017, 2001.
80.Teague, R. M., Sather, B. D., Sacks, J. A., Huang, M. Z., Dossett, M. L., Morimoto, J., Tan, X., Sutton, S. E., Cooke, M. P., Ohlen, C., and Greenberg, P. D. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med, 12: 335-341, 2006.
81.McInnes, I. B., Gracie, J. A., Harnett, M., Harnett, W., and Liew, F. Y. New strategies to control inflammatory synovitis: interleukin 15 and beyond. Ann Rheum Dis, 62 Suppl 2: ii51-54, 2003.
82.Jinushi, M., Takehara, T., Tatsumi, T., Kanto, T., Groh, V., Spies, T., Suzuki, T., Miyagi, T., and Hayashi, N. Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J Immunol, 171: 5423-5429, 2003.
83.Walzer, T., Dalod, M., Robbins, S. H., Zitvogel, L., and Vivier, E. Natural-killer cells and dendritic cells: "l''union fait la force". Blood, 106: 2252-2258, 2005.
84.Gosselin, J., TomoIu, A., Gallo, R. C., and Flamand, L. Interleukin-15 as an activator of natural killer cell-mediated antiviral response. Blood, 94: 4210-4219, 1999.
85.Kirman, I., Vainer, B., and Nielsen, O. H. Interleukin-15 and its role in chronic inflammatory diseases. Inflamm Res, 47: 285-289, 1998.
86.Ye, S. K., Maki, K., Lee, H. C., Ito, A., Kawai, K., Suzuki, H., Mak, T. W., Chien, Y., Honjo, T., and Ikuta, K. Differential roles of cytokine receptors in the development of epidermal gamma delta T cells. J Immunol, 167: 1929-1934, 2001.
87.Ahrar, K., Madoff, D. C., Gupta, S., Wallace, M. J., Price, R. E., and Wright, K. C. Development of a large animal model for lung tumors. J Vasc Interv Radiol, 13: 923-928, 2002.
88.Yajima, T., Yoshihara, K., Nakazato, K., Kumabe, S., Koyasu, S., Sad, S., Shen, H., Kuwano, H., and Yoshikai, Y. IL-15 regulates CD8+ T cell contraction during primary infection. J Immunol, 176: 507-515, 2006.
89.Marrack, P. and Kappler, J. Control of T cell viability. Annu Rev Immunol, 22: 765-787, 2004.
90.Demirci, G. and Li, X. C. IL-2 and IL-15 exhibit opposing effects on Fas mediated apoptosis. Cell Mol Immunol, 1: 123-128, 2004.
91.Sato, N., Patel, H. J., Waldmann, T. A., and Tagaya, Y. The IL-15/IL-15R{alpha} on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc Natl Acad Sci U S A, 104: 588-593, 2007.
92.Eberl, G., Brawand, P., and MacDonald, H. R. Selective bystander proliferation of memory CD4+ and CD8+ T cells upon NK T or T cell activation. J Immunol, 165: 4305-4311, 2000.
93.Tamang, D. L., Redelman, D., Alves, B. N., Vollger, L., Bethley, C., and Hudig, D. Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal. Cytokine, 2006.
94.Frey, M., Packianathan, N. B., Fehniger, T. A., Ross, M. E., Wang, W. C., Stewart, C. C., Caligiuri, M. A., and Evans, S. S. Differential expression and function of L-selectin on CD56bright and CD56dim natural killer cell subsets. J Immunol, 161: 400-408, 1998.
95.Mattei, F., Schiavoni, G., Belardelli, F., and Tough, D. F. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol, 167: 1179-1187, 2001.
96.Watson, R. W., Rotstein, O. D., Parodo, J., Bitar, R., and Marshall, J. C. The IL-1 beta-converting enzyme (caspase-1) inhibits apoptosis of inflammatory neutrophils through activation of IL-1 beta. J Immunol, 161: 957-962, 1998.
97.Bouchard, A., Ratthe, C., and Girard, D. Interleukin-15 delays human neutrophil apoptosis by intracellular events and not via extracellular factors: role of Mcl-1 and decreased activity of caspase-3 and caspase-8. J Leukoc Biol, 75: 893-900, 2004.
98.Ratthe, C. and Girard, D. Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Ralpha chain. J Leukoc Biol, 76: 162-168, 2004.
99.Munger, W., DeJoy, S. Q., Jeyaseelan, R., Sr., Torley, L. W., Grabstein, K. H., Eisenmann, J., Paxton, R., Cox, T., Wick, M. M., and Kerwar, S. S. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2. Cell Immunol, 165: 289-293, 1995.
100.Kimura, K., Nishimura, H., Hirose, K., Matsuguchi, T., Nimura, Y., and Yoshikai, Y. Immunogene therapy of murine fibrosarcoma using IL-15 gene with high translation efficiency. Eur J Immunol, 29: 1532-1542, 1999.
101.Fehniger, T. A., Suzuki, K., VanDeusen, J. B., Cooper, M. A., Freud, A. G., and Caligiuri, M. A. Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis, 27: 223-230, 2001.
102.Yoshimuta, T. Gene therapy for murine lung cancer using an adenoviral vector expressing interleukin-15. Kurume Med J, 51: 225-233, 2004.
103.van den Broeke, L. T., Daschbach, E., Thomas, E. K., Andringa, G., and Berzofsky, J. A. Dendritic cell-induced activation of adaptive and innate antitumor immunity. J Immunol, 171: 5842-5852, 2003.
104.Murgia, C., Pritchard, J. K., Kim, S. Y., Fassati, A., and Weiss, R. A. Clonal origin and evolution of a transmissible cancer. Cell, 126: 477-487, 2006.
105.Holmes, J. M. Measurement of the rate of death of canine transmissible venereal tumour cells transplanted into dogs and nude mice. Res Vet Sci, 30: 248-250, 1981.
106.Liao, K. W., Hung, S. W., Hsiao, Y. W., Bennett, M., and Chu, R. M. Canine transmissible venereal tumor cell depletion of B lymphocytes: molecule(s) specifically toxic for B cells. Vet Immunol Immunopathol, 92: 149-162, 2003.
107.Hsiao, Y. W., Liao, K. W., Hung, S. W., and Chu, R. M. Effect of tumor infiltrating lymphocytes on the expression of MHC molecules in canine transmissible venereal tumor cells. Vet Immunol Immunopathol, 87: 19-27, 2002.
108.Chandler, J. P. and Yang, T. J. Canine transmissible venereal sarcoma: distribution of T and B lymphocytes in blood, draining lymph nodes and tumours at different stages of growth. Br J Cancer, 44: 514-521, 1981.
109.Poggi, A. and Zocchi, M. R. Mechanisms of tumor escape: role of tumor microenvironment in inducing apoptosis of cytolytic effector cells. Arch Immunol Ther Exp (Warsz), 54: 323-333, 2006.
110.蕭雅文 犬傳染性花柳性腫瘤不同生長時期的腫瘤細胞與腫瘤浸潤淋巴球之交互作用. 國立台灣大學獸醫學研究所 博士論文, 2004.
111.Eisele, G., Wischhusen, J., Mittelbronn, M., Meyermann, R., Waldhauer, I., Steinle, A., Weller, M., and Friese, M. A. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain, 129: 2416-2425, 2006.
112.林靜宜 and 朱瑞民 合併使用IL-6及IL-15對受腫瘤來源TGF-β抑制之NK細胞活性的活化效應. 國立台灣大學獸醫學研究所 碩士論文, 2003
113.莊添富, 陶秘華, and 朱瑞民 使用腫瘤內電衝法轉染人類IL-12基因治療犬傳染性花柳性腫瘤. 國立台灣大學獸醫學研究所 碩士論文, 2005
114.Wells, D. J. Gene therapy progress and prospects: electroporation and other physical methods. Gene Ther, 11: 1363-1369, 2004.
115.Liu, X. H., Kirschenbaum, A., Yao, S., and Levine, A. C. The role of the interleukin-6/gp130 signaling pathway in bone metabolism. Vitam Horm, 74: 341-355, 2006.
116.Golzio, M., Teissie, J., and Rols, M. P. Direct visualization at the single-cell level of electrically mediated gene delivery. Proc Natl Acad Sci U S A, 99: 1292-1297, 2002.
117.Prud''homme, G. J., Glinka, Y., Khan, A. S., and Draghia-Akli, R. Electroporation-enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene Ther, 6: 243-273, 2006.
118.Gabriel, B. and Teissie, J. Direct observation in the millisecond time range of fluorescent molecule asymmetrical interaction with the electropermeabilized cell membrane. Biophys J, 73: 2630-2637, 1997.
119.Tekle, E., Astumian, R. D., and Chock, P. B. Electro-permeabilization of cell membranes: effect of the resting membrane potential. Biochem Biophys Res Commun, 172: 282-287, 1990.
120.Fox, M. B., Esveld, D. C., Valero, A., Luttge, R., Mastwijk, H. C., Bartels, P. V., van den Berg, A., and Boom, R. M. Electroporation of cells in microfluidic devices: a review. Anal Bioanal Chem, 385: 474-485, 2006.
121.Ahmad, M., Rees, R. C., and Ali, S. A. Escape from immunotherapy: possible mechanisms that influence tumor regression/progression. Cancer Immunol Immunother, 53: 844-854, 2004.
122.Moretta, L., Bottino, C., Pende, D., Vitale, M., Mingari, M. C., and Moretta, A. Human natural killer cells: Molecular mechanisms controlling NK cell activation and tumor cell lysis. Immunol Lett, 100: 7-13, 2005.
123.Gajewski, T. F., Meng, Y., and Harlin, H. Immune suppression in the tumor microenvironment. J Immunother, 29: 233-240, 2006.
124.Elliott, R. L. and Blobe, G. C. Role of transforming growth factor Beta in human cancer. J Clin Oncol, 23: 2078-2093, 2005.
125.Stalinska, L. and Ferenc, T. [The role of TGF-beta in cell cycle regulation]. Postepy Hig Med Dosw (Online), 59: 441-449, 2005.
126.Bello-DeOcampo, D. and Tindall, D. J. TGF-betal/Smad signaling in prostate cancer. Curr Drug Targets, 4: 197-207, 2003.
127.Souchelnytskyi, S. Proteomics of TGF-beta signaling and its impact on breast cancer. Expert Rev Proteomics, 2: 925-935, 2005.
128.Narayan, S., Thangasamy, T., and Balusu, R. Transforming growth factor -beta receptor signaling in cancer. Front Biosci, 10: 1135-1145, 2005.
129.Verrecchia, F. [Functional interactions between the TGF-beta signaling pathway via the Smads and TNF-alpha: implications for the regulation of type I collagen expression]. J Soc Biol, 199: 329-336, 2005.
130.Ugen, K. E., Kutzler, M. A., Marrero, B., Westover, J., Coppola, D., Weiner, D. B., and Heller, R. Regression of subcutaneous B16 melanoma tumors after intratumoral delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene Ther, 13: 969-974, 2006.
131.Nakano, H., Kishida, T., Asada, H., Shin-Ya, M., Shinomiya, T., Imanishi, J., Shimada, T., Nakai, S., Takeuchi, M., Hisa, Y., and Mazda, O. Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinoma. J Gene Med, 8: 90-99, 2006.
132.Kishida, T., Asada, H., Itokawa, Y., Cui, F. D., Shin-Ya, M., Gojo, S., Yasutomi, K., Ueda, Y., Yamagishi, H., Imanishi, J., and Mazda, O. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma. Mol Ther, 8: 552-558, 2003.
133.Mulders, P., Tso, C. L., Pang, S., Kaboo, R., McBride, W. H., Hinkel, A., Gitlitz, B., Dannull, J., Figlin, R., and Belldegrun, A. Adenovirus-mediated interleukin-2 production by tumors induces growth of cytotoxic tumor-infiltrating lymphocytes against human renal cell carcinoma. J Immunother, 21: 170-180, 1998.
134.Sutherland, C. L., Rabinovich, B., Chalupny, N. J., Brawand, P., Miller, R., and Cosman, D. ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. Blood, 108: 1313-1319, 2006.
135.Casale, T. B. and Carolan, E. J. Combination of IL-8 plus TNF alpha induces additive neutrophil migration. Allergy Asthma Proc, 20: 361-363, 1999.
136.Krieger, M., Brunner, T., Bischoff, S. C., von Tscharner, V., Walz, A., Moser, B., Baggiolini, M., and Dahinden, C. A. Activation of human basophils through the IL-8 receptor. J Immunol, 149: 2662-2667, 1992.
137.Mukaida, N., Harada, A., and Matsushima, K. Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions. Cytokine Growth Factor Rev, 9: 9-23, 1998.
138.Schratzberger, P., Dunzendorfer, S., Reinisch, N., Kahler, C. M., and Wiedermann, C. J. Interleukin-8-induced human peripheral blood B-lymphocyte chemotaxis in vitro. Immunol Lett, 58: 167-170, 1997.
139.Taub, D. D., Anver, M., Oppenheim, J. J., Longo, D. L., and Murphy, W. J. T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo. J Clin Invest, 97: 1931-1941, 1996.
140.Mariani, E., Pulsatelli, L., Meneghetti, A., Dolzani, P., Mazzetti, I., Neri, S., Ravaglia, G., Forti, P., and Facchini, A. Different IL-8 production by T and NK lymphocytes in elderly subjects. Mech Ageing Dev, 122: 1383-1395, 2001.
141.Nabors, L. B., Suswam, E., Huang, Y., Yang, X., Johnson, M. J., and King, P. H. Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR. Cancer Res, 63: 4181-4187, 2003.
142.Strandberg, K., Palmberg, L., and Larsson, K. Effect of formoterol and salmeterol on IL-6 and IL-8 release in airway epithelial cells. Respir Med, 2007.
143.Pauls, E., Senserrich, J., Bofill, M., Clotet, B., and Este, J. A. Induction of interleukins IL-6 and IL-8 by siRNA. Clin Exp Immunol, 147: 189-196, 2007.
144.Dragulev, B., Bao, Y., Ramos-Cerrillo, B., Vazquez, H., Olvera, A., Stock, R., Algaron, A., and Fox, J. W. Upregulation of IL-6, IL-8, CXCL1, and CXCL2 Dominates Gene Expression in Human Fibroblast Cells Exposed to Loxosceles reclusa Sphingomyelinase D: Insights into Spider Venom Dermonecrosis. J Invest Dermatol, 2006.
145.Sakoda, K., Yamamoto, M., Negishi, Y., Liao, J. K., Node, K., and Izumi, Y. Simvastatin decreases IL-6 and IL-8 production in epithelial cells. J Dent Res, 85: 520-523, 2006.
146.Melief, C. J. Mini-review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming? Eur J Immunol, 33: 2645-2654, 2003.
147.Weninger, W., Manjunath, N., and von Andrian, U. H. Migration and differentiation of CD8+ T cells. Immunol Rev, 186: 221-233, 2002.
148.Uhlin, M., Masucci, M., and Levitsky, V. Is the activity of partially agonistic MHC:peptide ligands dependent on the quality of immunological help? Scand J Immunol, 64: 581-587, 2006.
149.Kobel, M., Budianto, D., Schmitt, W. D., Borsi, L., Siri, A., and Hauptmann, S. Influence of various cytokines on adhesion and migration of the colorectal adenocarcinoma cell line HRT-18. Oncology, 68: 33-39, 2005.