摘要
肝細胞癌(hepatocellular carcinoma)和病毒性肝炎(viral hepatitis)在台灣都是重要的疾病，因此我們希望對肝臟浸潤淋巴細胞的性質加以探討。在本研究中，我們以酵素分解及梯度離心的方法分離出這些浸潤的淋巴細胞並分析之，以探討其活化及召集的機制。實驗結果顯示由腫瘤組織及非腫瘤組織所分離出的浸潤淋巴細胞大部份為活化的T細胞，並且是以分泌IFNg的Th1和Tc1細胞為主。而在肝臟腫瘤組織中的浸潤淋巴球(tumor-infiltrating lymphocyte，TIL)有較高比例的CD3+ (p＜0.05)及CD4+ T細胞(p＜0.001)，在非腫瘤的肝臟組織所分離出的浸潤淋巴細胞(liver-infiltrating lymphocyte，LIL)則有較高比例的CD56+細胞(p＜0.01)。此外我們發現不論是在腫瘤及非腫瘤組織中，CD4+，CD8+，CD56+的浸潤淋巴細胞均會表現趨化激素受器CXCR6。LIL中CD56+細胞表現CXCR6的比例高於TIL中的CD56+細胞(p<0.05)。CXCR6在TIL的CD4+細胞和LIL中的CD56+細胞的表現情況正好和CD4+細胞及CD56+細胞在TIL和LIL中所佔的比例呈正相關，因此TIL和LIL的細胞組成不同可能部份導因於CXCR6在TIL和LIL中各細胞次群的表現量有所不同。我們利用RT-PCR測量CXCR6所對應的趨化激素CXCL16的表現情形，結果發現肝臟腫瘤及非腫瘤組織中均有CXCL16的表現，而在未經過活化的PBMC中則否。我們同時發現肝臟腫瘤及非腫瘤組織中有IL-18的表現。當我們用plate-bound Anti-CD3活化周邊血液單核細胞時，同時加入IL-2及IL-18會使得CXCR6的表現量比單獨加入IL-2時來得低(p＜0.05)，這顯示在淋巴細胞活化時IL-18的存在與否仍然可能影響到CXCR6的表現量。最後，在利用刀豆素(Concanavalin A, Con A)在C57BL/6小鼠引發肝炎時，利用RT-PCR可以觀察到CXCR6在肝臟及脾臟的表現量均有提升，顯示CXCR6和CXCL16的交互作用不論在人類和小鼠均和肝臟浸潤淋巴細胞的活化與召集密切相關。以上的研究結果將有助於我們進一步了解肝臟浸潤淋巴細胞活化與召集的相關機制。

Abstract
Hepatocellular carcinoma and viral hepatitis both were important diseases in Taiwan. Therefore, we were interested in studying the characteristics of liver-infiltrating lymphocytes. In this study, we used enzymatic digestion and discontinuous centrifugation to isolate these infiltrating lymphocytes and then study the mechanism of the activation and recruitment of liver-infiltrating lymphocytes. Our results indicated that both tumor-infiltrating lymphocytes (TILs) and liver-infiltrating lymphocytes (LILs) from non-tumor part of liver were composed mainly of activated Th1 and Tc1 cells which secreting the cytokine interferon-g. There were significantly more CD3+ (p<0.05) and CD4+ T cells (p<0.001) in TILs than in LILs. In contrast, the LILs contained significantly more CD56+ cells (p<0.01) than in TILs. Besides, we found that a large part of CD4+, CD8+ and CD56+ cells in both TILs and LILs expressed the chemokine receptor CXCR6. The percentage of CXCR6+ cells in CD56+ cells was significantly higher in LILs than in TILs (p<0.05). The expression of CXCR6 in CD4+ cells in TILs and in CD56+ cells in LILs paralleled the percentages of these cells in total infiltrating lymphocytes. This result indicated that the different composition of lymphocyte subpopulation in TILs and LILs could be partially contributed to the differential expression pattern of CXCR6 in each subpopulation. The ligand of CXCR6 was CXCL16. We could detect CXCL16 expression by RT-PCR in both tumor and non-tumor part of liver but not unstimulated PBMCs. We also found IL-18 expression in both tumor and non-tumor part of liver by RT-PCR. When we used plate-bound Anti-CD3 and different cytokines to activate PBMCs, percentage of CXCR6+ cells was significantly lower in PBMCs treated with IL-2 plus IL-18 than in PBMCs treated with IL-2 alone (p<0.05). This suggested that the presence of IL-18 during lymphocyte activation might influence the expression of CXCR6 indirectly. We also showed that the expression of CXCR6 was up-regulated in liver and spleen in Con A induced hepatitis in mice. This indicated that the interaction between CXCR6 and CXCL16 might be involved in the activation and recruitment of liver-infiltrating lymphocytes in both human and mice. Our study would be helpful for further study of the mechanism of activation and recruitment of liver-infiltrating lymphocytes.

目 錄
口試委員會審定書…………………………………………………. i
授權書………………………………………………………………. ii
誌謝…………………………………………………………………. iv
中文摘要…………………………………………………………….vi
英文摘要…………………………………………………………….viii
第一章 緒論………………………………………………………. 1
第一節 研究背景與相關研究……………………………….. 1
一、肝臟浸潤淋巴細胞的組成……………..…………….. 1
二、肝臟浸潤淋巴細胞與病毒性肝炎………….……….. 2
三、肝細胞癌及腫瘤浸潤淋巴細胞…….……………….. 3
四、肝臟浸潤淋巴細胞召集的可能機制……………….. 5
五、趨化激素受器CXCR6及趨化激素CXCL16…….... 8
六、以刀豆素在小鼠建立肝炎的動物模式…………..…. 10
第二節 研究動機與目的…………………………………….. 12
第二章 實驗材料與方法…………………………………………. 14
第一節 實驗材料…………………………………………….. 14
一、 檢體來源及病人特徵………………………………... 14
二、 實驗小鼠……………………………………………... 14
三、 抗體及細胞激素……………………………………... 14
四、 試劑與藥品配方……………………………………... 16
(1)試劑………………………………………………... 16
(2)藥品配方…………………………………………... 20
五、 儀器…………………………………………………... 22
六、 耗材…………………………………………………... 24
第二節 實驗方法…………………………………………….. 25
一、 免疫組織化學染色..…………………………………. 25
二、 分離人類周邊血液單核細胞……………………….. 25
三、 分離人類肝細胞癌內的腫瘤浸潤淋巴細胞與非腫
瘤肝組織中所浸潤的淋巴細胞……………………... 26
四、 表面標記染色………………………..………………. 26
五、 胞內細胞激素染色……………….………………….. 27
六、 反轉錄及聚合酵素連鎖反應……………….……….. 27
(1)RNA之萃取…………………..…..………………. 27
(2)RNA之定量……………………....………………. 28
(3)反轉錄反應………………………..………………. 28
(4)聚合酵素連鎖反應………………..………………. 29
七、 周邊血液單核細胞培養………..……………………. 30
八、 利用刀豆素引發的肝炎及其評估…………...……… 31
九、 統計分析方法………………………………………... 31
第三章 實驗結果……………………………………….………… 32
第一節 肝臟浸潤淋巴細胞之特性………………………..… 32
一、肝臟浸潤淋巴細胞之分布…..……....………………. 32
二、肝臟浸潤淋巴細胞之表面標記分析…....……..……. 33
三、肝臟浸潤淋巴細胞之活化標記分析....……..………. 34
四、肝臟浸潤淋巴細胞之細胞激素分泌情況………..…. 34
第二節 趨化激素受器CXCR6及其相關因子的表現情形... 36
一、 肝臟浸潤淋巴細胞中趨化激素CXCR6的表
現情形………………………………………………... 36
二、 肝細胞癌組織及非腫瘤肝組織內趨化激素CXCL16
及細胞激素IL-18的表現情形………….…………... 37
三、 IL-18與趨化激素受器CXCR6表現量的關係..….... 38
第三節 趨化激素受器CXCR6在小鼠肝炎動物模式中的
表現情形…………………………..…………………. 40
第四章 討論…………………………………………….………… 42
第一節 肝臟浸潤淋巴細胞的基本特質…………………….. 42
第二節 趨化激素受器CXCR6與趨化激素CXCL16在肝
臟浸潤淋巴細胞的活化與召集之中可能扮演的角
色…………………………..…………………………. 46
第三節 IL-18與趨化激素受器CXCR6表現量的關係…..... 50
第四節 趨化激素受器CXCR6在刀豆素引發之肝炎的
表現情形…………………………………………….. 54
第五節 未來展望…………………………………………….. 61
第五章 參考文獻…………………………………………………. 62
第六章 圖表與說明……………………………………

Akriviadis, E.A., Llovet, J.M., Efremidis, S.C., Shouval, D., Canelo, R., Ringe, B., and Meyers, W.C. (1998). Hepatocellular carcinoma. Br. J. Surg. 85, 1319-1331.
Baecher-Allan, C., Brown, J.A., Freeman, G.J., and Hafler, D.A. (2001). CD4+CD25high regulatory cells in human peripheral blood. J.Immunol. 167, 1245-1253.
Barnaba, V., Franco, A., Paroli, M., Benvenuto, R., De Petrillo, G., Burgio, V.L., Santilio, I., Balsano, C., Bonavita, M.S., Cappelli, G., and et al. (1994). Selective expansion of cytotoxic T lymphocytes with a CD4+CD56+ surface phenotype and a T helper type 1 profile of cytokine secretion in the liver of patients chronically infected with Hepatitis B virus. J. Immunol. 152, 3074-3087.
Bertoletti, A., and Maini, M.K. (2000). Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr. Opin. Immunol. 12, 403-408.
Butcher, E.C., and Picker, L.J. (1996). Lymphocyte homing and homeostasis. Science 272, 60-66.
Bystry, R.S., Aluvihare, V., Welch, K.A., Kallikourdis, M., and Betz, A.G. (2001). B cells and professional APCs recruit regulatory T cells via CCL4. Nat. Immunol. 2, 1126-1132.
Calabresi, P.A., Yun, S.H., Allie, R.,and Whartenby, K.A. (2002). Chemokine receptor expression on MBP-reactive T cells: CXCR6 is a marker of IFNgamma-producing effector cells. J. Neuroimmunol. 127:96-105.
Campbell, J.J., Bowman, E.P., Murphy, K., Youngman, K.R., Siani, M.A., Thompson, D.A., Wu, L., Zlotnik, A., and Butcher, E.C. (1998). 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3beta receptor CCR7. J. Cell. Biol. 141, 1053-1059.
Campbell, J.J., and Butcher, E.C. (2000). Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr. Opin. Immunol. 12, 336-341.
Campbell, J.J., Haraldsen, G., Pan, J., Rottman, J., Qin, S., Ponath, P., Andrew, D.P., Warnke, R., Ruffing, N., Kassam, N., Wu, L., and Butcher, E.C. (1999). The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature. 400, 776-780.
Chen, D., McKallip, R.J., Zeytun, A., Do, Y., Lombard, C., Robertson, J. L., Mak, T.W., Nagarkatti, P.S., and Nagarkatti, M. (2001). CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death. J. Immunol. 166, 5889-5897.
Curry, M.P., Norris, S., Golden-Mason, L., Doherty, D.G., Deignan, T., Collins, C., Traynor, O., McEntee, G.P., Hegarty, J.E., and O’Farrelly, C. (2000). Isolation of lymphocytes from normal adult human liver suitable for phenotypic and functional characterization. J. Immunol. Methods. 242, 21-31.
Deng, H.K., Unutmaz, D., KewalRamani, V.N., and Littman, D.R. (1997). Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature. 388, 296-300.
Doherty, D.G., Norris, S., Madrigal-Estebas, L., McEntee, G., Traynor, O., Hegarty, J.E., and O’Farrelly, C. (1999). The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J. Immunol. 163, 2314-2321.
Doherty, D.G., and O’Farrelly, C. (2000). Innate and adaptive lymphoid cells in the human liver. Immunol. Rev. 174, 5-20.
Emoto, M., Miyamoto, M., Namba, K., Schmits, R., Van Rooijen, N., Kita, E., and Kaufmann, S.H. (2000). Participation of leukocyte function-associated antigen-1 and NK cells in the homing of thymic CD8+NKT cells to the liver. Eur. J. Immunol. 30, 3049-3056.
Erickson, A.L., Kimura, Y., Igarashi, S., Eichelberger, J., Houghton, M., Sidney, J., McKinney, D., Sette, A., Hughes, A.L., and Walker C.M. (2001). The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity. 15:883-895.
Fabbri, M., Bianchi, E., Fumagalli, L., and Pardi, R. (1999). Regulation of lymphocyte traffic by adhesion molecules. Inflamm. Res. 48, 239-246.
Grant, A.J., Lalor, P.F., Hubscher, S.G., Briskin, M., and Adams, D.H. (2001). MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology. 33, 1065-1072.
Hata, K., Zhang, X.R., Iwatsuki, S., Van Thiel, D.H., Herberman, R.B., and Whiteside, T.L. (1990). Isolation, phenotyping, and functional analysis of lymphocytes from human liver. Clin. Immunol. Immunopathol. 56, 401-419.
He, X.S., Rehermann, B., Lopez-Labrador, F.X., Boisvert, J., Cheung, R., Mumm, J., Wedemeyer, H., Berenguer, M., Wright, T.L., Davis, M.M., and Greenberg, H.B. (1999). Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers. Proc. Natl. Acad. Sci. USA. 96, 5692-5697.
Heydtmann, M., and Adams, D.H. (2002). Understanding selective trafficking of lymphocyte subsets. Gut. 50, 150-152.
Hornei, B., Kammerer, R., Moubayed, P., Frings, W., Gauss-Muller, V., and Dotzauer, A. (2001). Experimental hepatitis A virus infection in guinea pigs. J. Med. Virol. 64:402-409.
Hoshino, T., Kawase, Y., Okamoto, M., Yokota, K., Yoshino, K., Yamamura, K., Miyazaki, J., Young, H.A., and Oizumi, K. (2001). Cutting edge: IL-18-transgenic mice: in vivo evidence of a broad role for IL-18 in modulating immune function. J. Immunol. 166, 7014-7018.
Hoshino, T., Wiltrout, R.H., and Young, H.A. (1999). IL-18 is a potent coinducer of IL-13 in NK and T cells: a new potential role for IL-18 in modulating the immune response. J. Immunol. 162, 5070-5077.
Kim, C.H., Kunkel, E.J., Boisvert, J., Johnston, B., Campbell, J.J., Genovese, M.C., Greenberg, H.B., and Butcher, E.C. (2001). Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J. Clin. Invest. 107, 595-601.
Knolle, P.A., Gerken, G., Loser, E., Dienes, H.P., Gantner, F., Tiegs, G., Meyer zum Buschenfelde, K.H., and Lohse, A.W. (1996). Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice. Hepatology. 24, 824-829.
Kobayashi, N., Ito, M., Nakamura, J., Cai, J., Gao, C., Hammel, J.M., and Fox, I.J. (2000). Hepatocyte transplantation in rats with decompensated cirrhosis. Hepatology. 31:851-857.
Kunkel, E.J., and Butcher, E.C. (2002). Chemokines and the tissue-specific migration of lymphocytes. Immunity. 16:1-4.
Liao, F., Alkhatib, G., Peden, K.W., Sharma, G., Berger, E.A., and Farber, J.M. (1997). STRL33, A novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1. J. Exp. Med. 185, 2015-2023.
Loetscher, M., Amara, A., Oberlin, E., Brass, N., Legler, D., Loetscher, P., D'Apuzzo, M., Meese, E., Rousset, D., Virelizier, J.L., Baggiolini, M., Arenzana-Seisdedos, F., and Moser, B. (1997). TYMSTR, a putative chemokine receptor selectively expressed in activated T cells, exhibits HIV-1 coreceptor function. Curr. Biol. 7, 652-660.
Luster, A.D. (2002). The role of chemokines in linking innate and adaptive immunity. Curr. Opin. Immunol. 14:129-135.
Maini, M.K., Boni, C., Lee, C.K., Larrubia, J.R., Reignat, S., Ogg, G.S., King, A.S., Herberg, J., Gilson, R., Alisa, A., Williams, R., Vergani, D., Naoumov, N.V., Ferrari, C., and Bertoletti, A. (2000). The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J. Exp. Med. 191, 1269-1280.
Maini, M.K., Boni, C., Ogg, G.S., King, A.S., Reignat, S., Lee, C.K., Larrubia, J.R., Webster, G.J., McMichael, A.J., Ferrari, C., Williams, R., Vergani, D., and Bertoletti, A. (1999). Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology. 117, 1386-1396.
Matloubian, M., David, A., Engel, S., Ryan, J.E., and Cyster, J.G. (2000). A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat. Immunol. 1, 298-304.
Michalak, T.I. (2000). Occult persistence and lymphotropism of hepadnaviral infection: insights from the woodchuck viral hepatitis model. Immunol. Rev. 174:98-111.
Mizuhara, H., O'Neill E., Seki, N., Ogawa, T., Kusunoki, C., Otsuka, K., Satoh, S., Niwa, M., Senoh, H., and Fujiwara, H. (1994). T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J. Exp. Med. 179, 1529-1537.
Mizuhara, H., Uno, M., Seki, N., Yamashita, M., Yamaoka, M., Ogawa, T., Kaneda, K., Fujii, T., Senoh, H., and Fujiwara, H. (1996). Critical involvement of interferon gamma in the pathogenesis of T-cell activation-associated hepatitis and regulatory mechanisms of interleukin-6 for the manifestations of hepatitis. Hepatology. 23, 1608-1615.
Moser, B., and Loetscher, P. (2001). Lymphocyte traffic control by chemokines. Nat. Immunol. 2, 123-128.
Nicoletti, F., Zaccone, P., Xiang, M., Magro, G., Di Mauro, M., Di Marco, R., Garotta, G., Meroni, P. (2000). Essential pathogenetic role for interferon (IFN-)gamma in concanavalin A-induced T cell-dependent hepatitis: exacerbation by exogenous IFN-gamma and prevention by IFN-gamma receptor-immunoglobulin fusion protein. Cytokine. 12,315-323.
Norris, S., Collins, C., Doherty, D.G., Smith, F., McEntee, G., Traynor, O., Nolan, N., Hegarty, J., and O'Farrelly, C. (1998). Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J. Hepatol. 28, 84-90.
Okamoto, M., Kato, S., Oizumi, K., Kinoshita, M., Inoue, Y., Hoshino, K., Akira, S., McKenzie, A.N., Young, H.A., and Hoshino, T. (2002). Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia. Blood. 99, 1289-1298.
Okamoto, T., Yamamura, K., and Hino, O. (1999). The mouse interferon-gamma transgene chronic hepatitis model. Int. J. Mol. Med. 3:517-520.
Okuda, K. (2000). Hepatocellular carcinoma. J. Hepatol. 32, 225-237.
Penna, A., Del Prete, G., Cavalli, A., Bertoletti, A., D’Elios, M.M., Sorrentino, R., D’Amato, M., Boni, C., Pilli, M., Fiaccadori, F., and Ferrari, C. (1997). Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B. Hepatology. 25, 1022-1027.
Rabinowich, H., Cohen, R., Bruderman, I., Steiner, Z., and Klajman, A. (1987). Functional analysis of mononuclear cells infiltrating into tumors: lysis of autologous human tumor cells by cultured infiltrating lymphocytes. Cancer Res. 47, 173-177.
Read, S., and Powrie, F. (2001). CD4(+) regulatory T cells. Curr. Opin. Immunol. 13, 644-649.
Sharron, M., Pohlmann, S., Price, K., Lolis, E., Tsang, M., Kirchhoff, F., Doms, R.W., and Lee, B. (2000). Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. Blood. 96, 41-9.
Sheu, B.C., Hsu, S.M., Ho, H.N., Lien, H.C., Huang, S.C., and Lin, R.H. (2001). A novel role of metalloproteinase in cancer-mediated immunosuppression. Cancer Res. 61, 237-242.
Sheu, B.C., Lin, R.H., Ho, H.N., and Huang, S.C. (1997). Down-regulation of CD25 expression on the surface of activated tumor-infiltrating lymphocytes in human cervical carcinoma. Hum. Immunol. 56, 39-48.
Shields, P.L., Morland, C.M., Salmon, M., Qin, S., Hubscher, S.G., and Adams, D.H. (1999). Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J. Immunol. 163, 6236-6243.
Shimizu, Y., Iwatsuki, S., Herberman, R.B., and Whiteside, T.L. (1990). Clonal analysis of tumor-infiltrating lymphocytes from human primary and metastatic liver tumors. Int. J. Cancer. 46, 878-883.
Shimizu, Y., Iwatsuki, S., Herberman, R.B., and Whiteside, T.L. (1991). Effects of cytokines on in vitro growth of tumor-infiltrating lymphocytes obtained from human primary and metastatic liver tumors. Cancer. Immunol. Immunother. 32, 280-288.
Shimizu, Y., Murata, H., Kashii, Y., Hirano, K., Kunitani, H., Higuchi, K., and Watanabe, A. (2001). CC-chemokine receptor 6 and its ligand macrophage inflammatory protein 3alpha might be involved in the amplification of local necroinflammatory response in the liver. Hepatology. 34, 311-319.
Shimizu, Y., Watanabe, A., and Whiteside, T.L. (1992). Memory T-lymphocytes are the main population of tumor-infiltrating lymphocytes obtained from human primary liver tumors. J. Hepatol. 16, 197-202.
Shirabe, K., Matsumata, T., Maeda, T., Sadanaga, N., Kuwano, H., and Sugimachi, K. (1995). A long-term surviving patient with hepatocellular carcinoma including lymphocytes infiltration--a clinicopathological study. Hepatogastroenterology. 42, 996-1001.
Springer, T.A. (1994). Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 76, 301-314.
Tagawa, Y., Kakuta, S., and Iwakura, Y. (1998). Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis. Eur. J. Immunol. 28, 4105-4113.
Tiegs, G. (1997). Experimental hepatitis and role of cytokines. Acta. Gastroenterol. Belg. 60:176-9.
Tiegs, G., Hentschel, J., and Wendel, A. (1992). A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J. Clin. Invest. 90, 196-203.
Unutmaz, D., Xiang, W., Sunshine, M.J., Campbell, J., Butcher, E., and Littman, D.R. (2000). The primate lentiviral receptor Bonzo/STRL33 is coordinately regulated with CCR5 and its expression pattern is conserved between human and mouse. J. Immunol. 165, 3284-3292.
Ushio, S., Namba, M., Okura, T., Hattori, K., Nukada, Y., Akita, K., Tanabe, F., Konishi, K., Micallef, M., Fujii, M., Torigoe, K., Tanimoto, T., Fukuda, S., Ikeda, M., Okamura, H., and Kurimoto, M. (1996). Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J. Immunol. 156, 4274-4279.
Van Molle, W., Denecker, G., Rodriguez, I., Brouckaert, P., Vandenabeele, P., and Libert, C. (1999). Activation of caspases in lethal experimental hepatitis and prevention by acute phase proteins. J. Immunol. 163:5235-5241.
Wada, Y., Nakashima, O., Kutami, R., Yamamoto, O., and Kojiro, M. (1998). Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology. 27, 407-414.
Watanabe, Y., Morita, M., and Akaike, T. (1996). Concanavalin A induces perforin-mediated but not Fas-mediated hepatic injury. Hepatology. 24, 702-710.
Whiteside, T.L., Heo, D.S., Takagi, S., Johnson, J.T., Iwatsuki, S., and Herberman, R.B. (1988). Cytolytic antitumor effector cells in long-term cultures of human tumor-infiltrating lymphocytes in recombinant interleukin 2. Cancer. Immunol. Immunother. 26, 1-10.
Whiteside, T.L., Miescher, S., MacDonald, H.R., and Von Fliedner, V. (1986). Separation of tumor-infiltrating lymphocytes from tumor cells in human solid tumors. A comparison between velocity sedimentation and discontinuous density gradients. J. Immunol. Methods. 90, 221-233.
Wilbanks, A., Zondlo, S.C., Murphy, K., Mak, S., Soler, D., Langdon, P., Andrew, D.P., Wu, L., and Briskin, M. (2001). Expression cloning of the STRL33/BONZO/TYMSTR ligand reveals elements of CC, CXC, and CX3C chemokines. J. Immunol. 166, 5145-5154.
Wolf, D., Hallmann, R., Sass, G., Sixt, M., Kusters, S., Fregien, B., Trautwein, C., and Tiegs, G. (2001). TNF-alpha-induced expression of adhesion molecules in the liver is under the control of TNFR1--relevance for concanavalin A-induced hepatitis. J. Immunol. 166, 1300-1307.
Yoneyama, H., Narumi, S., Zhang, Y., Murai, M., Baggiolini, M., Lanzavecchia, A., Ichida, T., Asakura, H., and Matsushima, K. (2002). Pivotal role of dendritic cell-derived CXCL10 in the retention of T helper cell 1 lymphocytes in secondary lymph nodes. J. Exp. Med. 195:1257-1266.
Yoong, K.F., Afford, S.C., Jones, R., Aujla, P., Qin, S., Price, K., Hubscher, S.G., and Adams, D.H. (1999). Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma. Hepatology 30, 100-111.
Yoong, K.F., McNab, G., Hubscher, S.G., and Adams, D.H. (1998). Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J. Immunol. 160, 3978-3988.
Zabel, B.A., Agace, W.W., Campbell, J.J., Heath, H.M., Parent, D., Roberts, A.I., Ebert, E.C., Kassam, N., Qin, S., Zovko, M., LaRosa, G.J., Yang, L.L., Soler, D., Butcher, E.C., Ponath, P.D., Parker, C.M., and Andrew, D.P. (1999). Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J. Exp. Med. 190, 1241-1256.