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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許秉寧(Ping-Ning Hsu) | |
dc.contributor.author | Chi-Chang Sung | en |
dc.contributor.author | 宋奇璋 | zh_TW |
dc.date.accessioned | 2021-05-20T00:51:47Z | - |
dc.date.available | 2020-08-26 | |
dc.date.available | 2021-05-20T00:51:47Z | - |
dc.date.copyright | 2020-08-26 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-08-07 | |
dc.identifier.citation | Alter, H., Block, T., Brown, N., Brownstein, A., Brosgart, C., et al. (2018) A research agenda for curing chronic hepatitis B virus infection. Hepatology 67: 1127–1131 André, P., Denis, C., Soulas, C., Bourbon-Caillet, C., Lopez, J., et al. (2018) Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK Cells. Cell. 175(7): 1731–1743.e13 Andrews, D., Sullivan, L. Baschuk, N., Chan, C., Barry, R., et al. (2012). Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells. Nature immunology 13, 1171-1177. Ashwell, G., and Harford, J. (1982). Carbohydrate-specific receptors of the liver. Annu Rev Biochem. 51: 531-54. Biron, C., Byron, k., and Sullivan, J. (1989) Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med, 320(26): p. 1731-5. Beura, L., Wijeyesinghe, S., Thompson, E., Macchietto, M., Rosato, P., et al. (2018) T cells in nonlymphoid tissues give rise to lymph-node-resident memory T cells. Immunity. 48: 327-338 e325. Chang, MH., You, SL., Chen, CJ., Liu, CJ., Lee, CM., et al. (2009) Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: A 20-year follow-up study. J Natl Cancer Inst, 101: 1348–1355 Chang, TT., Liaw, YF., Wu, SS., Schiff, E., Han, KH., et al. (2010) Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 52(3):886-93. Chen, XP., Enioutina, E., and Daynes, R. (1997) The control of IL-4 gene expression in activated murine T lymphocytes: a novel role for neu-1 sialidase. J Immunol 58: 3070–3080. Chiossone, L., Chaix, J., Fuseri, N., Roth, C., Vivier, E., et al. (2009). Maturation of mouse NK cells is a 4-stage developmental program. Blood 113, 5488-5496. Chisari, F., and Ferrari, C. (1995). Hepatitis B virus immunopathogenesis. Annual review of immunology 13, 29-60. Chisari, F., Pinkert, C., Milich, D., Filippi, P, McLachlan, A., et al. (1985) A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. Science 230: 1157-1160. Chyuan, IT., Tsai, HF., Tzeng, HT., Sung, CC., Wu, CS., et al. (2015) Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model. Cell Mol Immunol 12(3): 317-25. Clark, R, Watanabe, R., Teague, J., Schlapbach, C., Tawa, M., et al. (2012) Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Trans. Med. 4, 117ra7 Crispe, I. (2003) Hepatic T cells and liver tolerance. Nat Rev Immunol 3(1):51-62 Dandri, M., Burda, M., Török, E., Pollok, J., Iwanska, A., et al. (2001) Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology 33: 981-988. Dansako, H., Ueda, Y., Okumura, N., Satoh, S., Sugiyama, M., et al. (2016) The cyclic GMP-AMP synthetase-STING signaling pathway is required for both the innate immune response against HBV and the suppression of HBV assembly. FEBS J. 283(1):144-56 Dusséaux, M, Masse-Ranson, G., Darche, S., Ahodantin, J., Li, Y., et al. (2017) Viral Load Affects the Immune Response to HBV in Mice With Humanized Immune System and Liver. Gastroenterology. 153: 1647–1661. Dunn, C., Peppa, D., Khanna, P., Nebbia, G., Jones, M., et al., (2009) Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 137(4): p. 1289-300. Ebert, G., Preston, S., Allison, C., Cooney, J., Toe, J., et al., (2015) Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus. PNAS 112(18): p. 5797-802. Fernandez-Ruiz, D.,Ng, WY., Holz, L., Ma, J., Zaid, A., et al., (2016) Liver-Resident Memory CD8(+) T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection. Immunity 45(4): p. 889-902. Forbes, C., Scalzo, A., Degli-Esposti, M., and Coudert, J. (2014). Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules. PLoS pathogens 10, e1004161. Freitas-Lopes, M., Mafra, K., David, B., Carvalho-Gontijo, R., and Menezes, G. (2017) Differential location and distribution of hepatic immune cells. Cells. 6(4): 48 Gane, E., Verdon, D., Brooks, A., Gagger, A, Nguyen, AH., et al. (2019) Anti-PD-1 Blockade With Nivolumab With and Without Therapeutic Vaccination for Virally Suppressed Chronic Hepatitis B: A Pilot Study. J Hepatol . 71(5): 900-907. Gao, Y.,Souza-Fonseca-Guimaraes, F., Bald, T., Ng, S., Young, A., et al. (2017). Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nature immunology 18, 1004-1015. Guidotti, L., Ando, K., Hobbs, M., Ishikawa, T., Runkel, L., et al. (1994) Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. PNAS 91(9): 3764-8 Guidotti, L., Rochford, R., Chung, J., Shapiro, M., Purcell, R., et al. (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science 284: 825-9 Guidotti, L., Inverso, D., Sironi, L., Lucia, P., Fioravanti, J., et al., (2015) Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell 161(3): p. 486-500. Guy, C., Rankin, S., and Michalak, T. (2011) Hepatocyte cytotoxicity is facilitated by asialoglycoprotein receptor. Hepatology. 54(3): 1043-50 Habu, S., Hayakawa, K., Okumura, K., and Tada, T. (1979) Surface markers on natural killer cells of the mouse. Eur J Immunol. 9(12):938-42. Holz, L., Prier, J, Freestone, D., Steiner, T., English, K., et al. (2018) CD8+ T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver. Cell Rep. 25: 68-79. Huang, LR., Wu, HL., Chen, PJ., and Chen, DS. (2006) An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. PNAS 103; 17862-17867. Johnson, D., Balko, J., Compton,M., Chalkias, S., Gorham, J., et al. (2016) Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016 375: 1749-1755 Kamizono, S., Duncan, G., Seidel, M., Morimoto, S., Koichi, H., et al. (2009) Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 206(13): 2977-2986 Kashii, Y., Giorda, R., Herberman, R., Whiteside, T., and Vujanovic, N. (1999) Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. J Immunol. 163(10): p. 5358-66. Kashiwada, M., Pham, N., Pewe, L., Harty, J., and Rothman, P. (2011) NFIL3/E4BP4 is a key transcription factor for CD8α⁺ dendritic cell development. Blood. 117(23): 6193-7 Keating, R., Yue, W., Rutigliano, J., So, J., Olivas, E., et al. (2007) Virus-specific CD8+ T cells in the liver: armed and ready to kill. J Immunol. 178: 2737-2745. El-Khoueiry, A., Sangro, B., Yau, T., Crocenzi, T., Kudo, M., et al. (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088): 2492-2502 Kiessling, R., Klein, E., and Wigzell, H. (1975). 'Natural' killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. European journal of immunology 5, 117-121. Kosaka, A., Wakita, D., Matsubara, N., Togashi, Y., Nishimura, S., et al., (2007) AsialoGM1+CD8+ central memory-type T cells in unimmunized mice as novel immunomodulator of IFN-gamma-dependent type 1 immunity. Int Immunol 19(3): p. 249-56. Lee-Sayer, S., Maeshima, N., Dougan, M., Dahiya, A., Arif, A., et al.,(2018) Hyaluronan-binding by CD44 reduces the memory potential of activated murine CD8 T cells. Eur J Immunol,.48: 803-14 Li, M., Sun, R., Xu, L., Yin, W., Chen, Y., et al., (2015) Kupffer cells support hepatitis B virus-mediated CD8+ T cell exhaustion via hepatitis B core antigen-TLR2 interactions in mice. J Immunol. 195(7): p. 3100-9. Lu, HL., and Liao, F. (2013) Melanoma differentiation-associated gene 5 senses hepatitis B virus and activates innate immune signaling to suppress virus replication. J Immunol 191: 3264-3276 Mackay, L., Rahimpour, A., Ma, J., Collins, N., Stock, A., et al. (2013) The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. Nat Immunol. 14: 1294-1301. Mackay, L., Minnich, M., Kragten, N., Liao, Y., Nota, B., et al. (2016) Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science. 352: 459-463. Malice, D., and McLachian, A. (1986) The nucleocapsid of hepatitis B virus is both a T-cell-independent and a T-cell-dependent antigen. Science. 234(4782): 1398-401. McNamara, H., Cai, Y., Wagle, M., Sontani, Y., Roots, C., et al., (2017) Up-regulation of LFA-1 allows liver-resident memory T cells to patrol and remain in the hepatic sinusoids. Sci Immunol 2(9). McVicker, B., Thiele, G., Casey, C., Osna, N., and Tuma, D. (2013) Susceptibility to T cell-mediated liver injury is enhanced in asialoglycoprotein receptor-deficient mice. Int Immunopharmacol.16(1): 17-26 Mueller, S., and Mackay, L. (2016) Tissue-resident memory T cells: local specialists in immune defence. Nat Rev Immunol. 16(2): 79-89. Nagafuku, M., Okuyama, K., Onimaru, Y., Suzuki, A., Odagiri, Y., et al. (2012) CD4 and CD8 T cells require different membrane gangliosides for activation. PNAS ;109(6): E336-42. Nishikado, H., Mukai, K., Kawano, Y., Minegishi Y., and Karasuyama, H. (2011) NK cell-depleting anti-asialo GM1 antibody exhibits a lethal off-target effect on basophils in vivo. J Immunol 186(10): p. 5766-71. Pagliaccetti, N., Chu, E., Bolen, C., Kleinstein, S., and Robek, M. (2010) λ and α interferons inhibit hepatitis B virus replication through a common molecular mechanism but with different in vivo activities. Virology 401: 197–206 Pallett, L., Davies, J., Colbeck, E., Robertson, F., Hansi, N., et al. (2017) IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection. J. Exp. Med. 214: 1567–1580. Peppa, D., Gill, U., Reynolds, G.,Easom, N., Pallet, L., et al., (2013) Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med, 210(1): p. 99-114. Perrillo, R., Gish, R., and Falck-Ytter, Y. et al. (2015) American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 148(1): 221-244.e3. Racanelli, V., and Rehermann, B. (2006) The liver as an immunological organ. Hepatology 43: S54-S62 Sato, S., Li, K., Kameyama, T., Hayashi, T., Ishida, Y., et al. (2015) The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 42: 123–132 Saunier, B., Triyatni, M., Ulianich, L., Maruvada, P., Yen, P., et al. (2003) Role of the asialoglycoprotein receptor in binding and entry of hepatitis C virus structural proteins in cultured human hepatocytes. J Virol. 77(1): 546-59 Schmidt, J., Blum, H., and Thimme, R. (2013) T-cell responses in hepatitis B and C virus infection: similarities and differences. Emerg. Microbes and Infect. 2: e15 Schmitz, A., Schwarz, A., Foss, M., Zhou, L, Rabe, B., et al. (2010). Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket. PLoS pathogens 6, e1000741. Seillet, C., Rankin, L., Groom, J., Mielke, L., Tellier, J., et al. (2014) Nfil3 is required for the development of all innate lymphoid cell subsets. J Exp Med. 211(9): 1733-40 Shin, E., Sung, P., and Park, S. (2016) Immune Responses and Immunopathology in Acute and Chronic Viral Hepatitis. Nat Rev Immunol. 16(8):509-23 Slifka, M., Pagarigan, R., and Whitton, J. (2000) NK markers are expressed on a high percentage of virus-specific CD8+ and CD4+ T cells. J Immunol, 164(4): p. 2009-15. Sprinzl, M., Oberwinkler,H., Schaller, H., and Protzer, U. (2001). Transfer of hepatitis B virus genome by adenovirus vectors into cultured cells and mice: crossing the species barrier. Journal of virology 75: 5108-5118. Spits, H., Artis, D., Colonna, M., Diefenbach, A., Di Santo, J., et al. (2013) Innate lymphoid cells - a proposal for uniform nomenclature. Nat Rev Immunol. 13 (2): 145–149. Strick-Marchand, H., Dusséaux, M., Darche, S., Huntington, N., Legrand, N., et al. (2015). A novel mouse model for stable engraftment of a human immune system and human hepatocytes. PloS one 10: e0119820. Takeda, K., Hayakawa, Y., Smyth, M., Kayagaki, N., Yamaguchi, N., et al. (2001). Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat. med. 7: 94-100. Takamiya, K., Yamamoto, A., Furukawa, K., Yamashiro, S., Shin, M., et al. (1996) Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. PNAS 93(6): 10662-1066 Thimme, R., Wieland, S., Steiger, C., Ghrayeb, J., Reimann, K., et al. (2003) CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 77(1): 68‐76 Topham, D., and Reilly, E. (2018) Tissue-resident memory CD8+ T cells: From phenotype to function. Front Immunol. 9: 515 Tzeng, HT., Tsai, HF., Liao, HJ., Lin, YL., Chen, LP., et al., (2012) PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model. PLoS One 7(6): p. e39179. Tzeng, HT., Tsai, HF., Chyuan, IT., Liao, HJ, Chen, CJ., et al., (2014) Tumor necrosis factor-alpha induced by hepatitis B virus core mediating the immune response for hepatitis B viral clearance in mice model. PLoS One. 9(7): p. e103008. Vivier, E., Raulet, D., Moretta, A., Caligiuri, M., Zitvogel, L., et al., (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331(6013): p. 44-9. Wang, R., Jaw, J., Stutzman, N., Zou, Z., Sun, P., et al. (2012). Natural killer cell-produced IFN-gamma and TNF-alpha induce target cell cytolysis through up-regulation of ICAM-1. J. Leukoc. Biol. 91: 299-309. Watashi, K., Liang, G., Iwamoto, M., Marusawa, H., Uchida, N., et al. (2013) Interleukin-1 and tumor necrosis factor-alpha trigger restriction of hepatitis B virus infection via a cytidine deaminase AID. J Biol Chem 288(44): 31715 Wei, S., Levine, J., Cogdill, A., Zhao, Y., Anang,N., et al., (2017) Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170(6): p. 1120-1133.e17. Wieland, S., Thimme, R., Purcell, R., and Chisari, F. (2004) Genomic analysis of the host response to hepatitis B virus infection. PNAS 101(17): p. 6669-74. Wu, LL., Peng, WH., Wu, HL., Miaw, SC., Yeh, SH., et al. Lymphocyte antigen 6 complex, locus C+ monocytes and Kupffer cells orchestrate liver immune responses against hepatitis B virus in mice. Hepatology 69(6): 2364-2380 Xu, L., Yin, W., Sun, R., Wei, H., and Tian Z. (2014) Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice. Hepatology 59(2): p. 443-52. Yan, H., Zhong, G., Xu, G., He, W., Jing, Z., et al. (2012). Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049. Yang, HI., Lu, SN., Liaw, YF., You, SL., Sun, CA., et al. (2002) Hepatitis B E Antigen and the Risk of Hepatocellular Carcinoma. N Engl J Med 347(3): 168-74 Yang J., Bo, X., Yao, J., Yang, N., and Wang S. (2005) Differentially expressed cellular genes following HBV: potential targets of anti-HBV drugs? J Viral Hepat. 12(4):357-63 Yang, P., Althage, A., Chung, J., Maier, H., Wieland, S., et al. (2010). Immune effectors required for hepatitis B virus clearance. PNAS 107: 798-802. Yeh, ML., Peng, CY., Dai, CY., Lai, HC., Hunag, CF., et al. (2015). Pegylated-interferon alpha therapy for treatment-experienced chronic hepatitis B patients. PloS one 10, e0122259. Zhang, W., Zhang, J., Lomuc, M., Kwan, K., Frank, R., et al. (1995) Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter. Mol. Cell. Biol.15: 6055–6063 Zhang, Q., Bi, J., Zheng, X., Chen, Y., Wang, H., et al. (2018) Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 19(7): 723-732 Zhang, T., Waard, A., Wuhrer, M., and Spaapen, R. (2019) The role of glycosphingolipids in immune cell functions. Front Immunol. 2019 10: 90 Zheng, M., Sun, R., Wei, H., and Tian, Z. (2016) NK Cells help induce anti-hepatitis B virus CD8+ T cell immunity in mice. J Immunol, 196(10): p. 4122-31. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8308 | - |
dc.description.abstract | HBV感染引起與慢性肝炎、肝硬化以及肝癌,造成全球性的健康問題。免疫系統如何控制病毒的機制知之甚少。以前的研究顯示,注射抗AsialoGM1(ASGM1)抗體可阻斷小鼠動物模型中HBV清除的能力,並且一般認為這是由於抗ASGM1導致NK細胞消失。為了進一步驗證NK細胞在HBV清除中的作用,在本研究中,我們使用NFIL3敲除(KO)小鼠(NK細胞缺乏的小鼠)來支持NK細胞對HBV的清除作用。意外的是,在NFIL3 KO小鼠中,清除HBV的能力沒有受到影響,表明NK細胞在HBV清除中不起關鍵作用。此外,用抗ASGM1處理的NFIL3 KO小鼠仍導致抗HBV抗性喪失,暗示存在其他非NK的ASGM1表達免疫細胞參與HBV清除。為了探討這個問題,我們對NFIL3 KO小鼠的肝內ASGM1 +細胞進行了分選,並分析了這些細胞的免疫表型,發現共表達CD44和LFA-1的肝臟駐留CD8 T細胞在這些細胞中佔多數。我們的研究表明, NK細胞在HBV清除中不是必需的。相反地,表達CD44和LFA-1的ASGM1陽性CD8 T細胞是參與抗HBV免疫的主要效應免疫細胞。重要的是,基因轉錄體分析,顯示ASGM1陽性CD8 T細胞相對其他細胞具有獨特的基因轉錄模式,比較像其他研究中所述的組織佇留T細胞(TRM)。我們進一步用過繼性細胞轉移的實驗證明,唯有來自肝臟的ASGM1陽性CD8 T細胞可以順利進入接受小鼠的肝臟中並有接近半數可存活超過二週,證明肝臟的ASGM1陽性CD8 T細胞確實擁有組織佇留的能力。總結以上幾點,我們認為NK細胞在HBV清除中並非關鍵的細胞,相對地,具有組織佇留能力的ASGM1陽性CD8 T細胞,同時表現CD44和LFA-1,在HBV清除中扮演重要的角色。根據本篇的研究,肝細胞上是何種接受子幫助ASGM1的結合,是未來可以進一步的探討的方向。 | zh_TW |
dc.description.abstract | Hepatitis B virus (HBV) infection causes chronic liver diseases that may progress to chronic hepatitis, liver cirrhosis, and subsequent hepatocellular carcinoma. Previous studies demonstrated that CD8 T cells are critical in HBV elimination. However, whether there is a distinct subtype of CD8 T cells response for the clearance of HBV remains unclear. In this study, we showed that the treatment with anti-asialo GM1(ASGM1) antibody (Ab), an NK cell-depleting Ab for ablating the function of NK cells in vivo, led to impairment of the ability to clear HBV in a mouse animal model. Unexpectedly, the ability to clear HBV was not significantly impaired in NFIL3 KO mice, which are deficient in NK cells, indicating that conventional NK cells do not play a critical role in HBV clearance. Moreover, the ability to clear HBV was abolished when NFIL3 KO mice were further treated with anti-ASGM1 Ab, implying that other non-NK ASGM1-positive immune cells mediate HBV clearance. We isolated intrahepatic ASGM1+ cells from the liver of NFIL3 KO mice and analyzed the immune phenotype of these cells. Our results demonstrated a distinct CD44+ LFA-1hi CD8 T cells that were the major intrahepatic ASGM1-positive immune cells. Importantly, transcriptome analysis revealed that ASGM1-positive CD8 T cells existed substantial differences from others and have similar core gene signature of tissue resident memory cells (TRM). Regarding ASGM1-positive CD8 T cells showed both transcriptional and phenotypic liver residency, we further proved that these cells indeed homed to and remained long-lasting in the liver after adoptive transferring. Collectively, our study indicates that conventional NK cells are not essential for HBV clearance in this mouse model. Instead, ASGM1-positive liver-resident CD8 T cells which express CD44 and LFA-1 are the major effector immune cells mediating anti-HBV immunity. The hepatic receptor which mediates the binding of ASGM1 will be investigated. | en |
dc.description.provenance | Made available in DSpace on 2021-05-20T00:51:47Z (GMT). No. of bitstreams: 1 U0001-0608202013302800.pdf: 5709401 bytes, checksum: 9f3a4faeceb2119f6824b127417d2b22 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 口試委員會審定書 i 誌謝 ii 中文摘要 iii Abstract v List of Figures x Chapter 1 Introduction 1 1.1 Hepatitis B virus (HBV)………………………………...………………….2 1.2 Host immunity against HBV………………………………………………4 1.3 Kupffer Cells and inflammatory monocytes plays opposite roles in HBV clearance……………………………………………………...……………7 1.4 Nature killer cells produce TNF-α, suggesting its role to control hepatitis B virus……………………………………….…………..………8 1.5 Hydrodynamically transfection animal models are used to explore the role of immune response after HBV transfection……………………...10 1.6 Tissue resident memory CD8 T cells (TRM) play important role in controlling intracellular pathogens……………………………………..12 Chapter 2 Materials and Methods 15 Chapter 3 Results 23 3.1 Anti-AsialoGM1(ASGM1) treatment resulted in lack of sustained HBsAg clearance from serum.……………………………...…………...24 3.2 NFIL3 KO mice remained immune-competent to eliminate HBV……………………………….………………………..……………..24 3.3 The non-NK ASGM1 positive immune cells mediated HBV clearance.25 3.4 The majority of intrahepatic ASGM1 positive immune cells in NFIL3 KO mice were CD8 T cells. …………..………………………..………..26 3.5 The intrahepatic ASGM1 positive CD8 T cells in HBV carrier mice expressed CD44 and LFA-1. …………………………………..………..27 3.6 The intrahepatic ASGM1, CD44 and LFA-1 triple positive CD8 T cells were a distinct sub-population. …………..……………………………..28 3.7 Intrahepatic ASGM1+ CD8 T cells had distinct transcriptional profile from ASGM1-CD8 T cells and showed similarity to core gene signature of TRM………..…………………………………...…………..29 3.8 Intrahepatic ASGM1+ CD8 T cells homed to and persisted in the liver after transplantation. …………………………...………………...……..30 3.9 Blocking of ASGPR1 dampened the liver homing of ASGM1+ CD8 T cells. …………………………...………..……………………..…...……..31 Chapter 4 Discussion 32 4.1 Contribution of this work…….……………………………...…………...33 4.2 Deficient of conventional NK cells is not enough to impair the ability of HBV clearance.………..………….………………………..……………..33 4.3 The role of distinct CD8 T subset in the immune response needs to be explore……………………………………………………………………34 4.4 TRM or liver resident CD8 T will be the potential target of immune therapy……………….…………..………………………..……………...36 References 62 | |
dc.language.iso | en | |
dc.title | 小鼠模式中表現無唾液酸神經節甘脂GM1的肝臟佇留CD8 T細胞對HBV的清除扮演必要的角色 | zh_TW |
dc.title | Asialo GM1-positive liver-resident CD8 T cells are essential for immune clearance of hepatitis B virus in a mouse model | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳培哲(Pei-Jer Chen),朱清良(Ching-Liang Chu),謝世良(Shie-Liang Hsieh),楊宏志(Hung-Chih Yang) | |
dc.subject.keyword | B型肝炎病毒HBV,高壓尾靜脈注射法小鼠模式,無唾液酸神經節甘脂GM1,NFIL3基因缺失小鼠,肝臟CD8 T細胞,去唾液酸糖蛋白受體, | zh_TW |
dc.subject.keyword | Hepatitis B virus,Hydrodynamic injection mouse model,Asialo GM1,Liver resident CD8 T cells,Asialoglycoprotein receptor, | en |
dc.relation.page | 79 | |
dc.identifier.doi | 10.6342/NTU202002529 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2020-08-10 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
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U0001-0608202013302800.pdf | 5.58 MB | Adobe PDF | 檢視/開啟 |
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