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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 莊雅惠(Ya-Hui Chuang) | |
dc.contributor.author | Chao-Hsuan Chang | en |
dc.contributor.author | 章肇軒 | zh_TW |
dc.date.accessioned | 2021-06-13T06:15:20Z | - |
dc.date.available | 2021-12-31 | |
dc.date.copyright | 2011-10-07 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-07-26 | |
dc.identifier.citation | 1.Crispe IN. 2009. The Liver as a Lymphoid Organ. Annual Review of Immunology 27: 147-63
2.Kaplan MM, Gershwin ME. 2005. Primary Biliary Cirrhosis. New England Journal of Medicine 353: 1261-73 3.Jones DEJ. 2008. Pathogenesis of primary biliary cirrhosis. Postgraduate Medical Journal 84: 23-33 4.Kaplan MM. 1996. Primary Biliary Cirrhosis. New England Journal of Medicine 335: 1570-80 5.Ludwig J. 1987. New Concepts in Biliary Cirrhosis. Semin Liver Dis 7: 293,301 6.Gershwin ME, Mackay IR, Sturgess A, Coppel RL. 1987. Identification and specificity of a cDNA encoding the 70 KD mitochondrial antigen recognized in primary biliary cirrhosis. Journal of Immunology 138: 3525-31 7.Jones DE. 2004. Primary Biliary Cirrhosis. Autoimmunity 37: 325-8 8.Palmer JM, Jones DE, Quinn J, McHugh A, Yeaman SJ. 1999. Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis. Hepatology 30: 21-6 9.Bruggraber SFA, Leung PSC, Amano K, Quan C, Kurth MJ, Nantz MH, Benson GD, Van de Water J, Luketic V, Roche TE, Ansari AA, Coppel RL, Gershwin ME. 2003. Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis. Gastroenterology 125: 1705-13 10.Quinn J, Diamond AG, Palmer JM, Bassendine MF, James OFW, Yeaman SJ. 1993. Lipoylated and unlipoylated domains of human PDC-E2 as autoantigens in primary biliary cirrhosis: Significance of lipoate attachment. Hepatology 18: 1384-91 11.Lleo A, Bowlus CL, Yang G-X, Invernizzi P, Podda M, Van de Water J, Ansari AA, Coppel RL, Worman HJ, Gores GJ, Gershwin ME. 2010. Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 52: 987-98 12.Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR, Gores GJ, Ansari AA, Van de Water J, Gershwin ME. 2009. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology 49: 871-9 13.Nagata S, Hanayama R, Kawane K. 2010. Autoimmunity and the Clearance of Dead Cells. Cell 140: 619-30 14.Lee JM, Dedhar S, Kalluri R, Thompson EW. 2006. The epithelial–mesenchymal transition: new insights in signaling, development, and disease. The Journal of Cell Biology 172: 973-81 15.Rygiel KA, Robertson H, Burt AD, Jones DEJ, Kirby JA. 2006. 650 Demonstration of the transition of intrahepatic biliary epithelial cells to fibroblasts during chronic inflammatory liver diseases. Journal of hepatology 44: S241 16.Robertson H, Kirby JA, Yip WW, Jones DEJ, Burt AD. 2007. Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis. Hepatology 45: 977-81 17.Joplin R, Strain A, Neuberger J, Lindsay JG, Johnson GD. 1992. Membrane dihydrolipoamide acetyltransferase (E2) on human biliary epithelial cells in primary biliary cirrhosis. The Lancet 339: 93-4 18.Klein R, Wiebel M, Engelhart S, Berg PA. 1993. Sera from patients with tuberculosis recognize the M2a-epitope (E2-subunit of pyruvate dehydrogenase) specific for primary biliary cirrhosis. Clinical & Experimental Immunology 92: 308-16 19.Goldblatt D, Thrasher AJ. 2000. Chronic granulomatous disease. Clinical & Experimental Immunology 122: 1-9 20.Reynoso-Paz S, Leung PSC, Van de Water J, Tanaka A, Munoz S, Bass N, Lindor K, Donald PJ, Coppel RL, Ansari AA, Gershwin ME. 2000. Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis. Hepatology 31: 24-9 21.Robe AJ, Kirby JA, Jones DEJ, Palmer JM. 2005. A key role for autoreactive B cells in the breakdown of T-cell tolerance to pyruvate dehydrogenase complex in the mouse. Hepatology 41: 1106-12 22.Jones DEJ, Palmer JM, James OFW, Yeaman SJ, Bassendine MF, Diamond AG. 1995. T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis. Hepatology 21: 995-1002 23.Kita H, Lian Z-X, Van de Water J, He X-S, Matsumura S, Kaplan M, Luketic V, Coppel RL, Ansari AA, Gershwin ME. 2002. Identification of HLA-A2–restricted CD8+ Cytotoxic T Cell Responses in Primary Biliary Cirrhosis. The Journal of Experimental Medicine 195: 113-23 24.Shimoda S, Van de Water J, Ansari A, Nakamura M, Ishibashi H, Coppel RL, Lake J, Keeffe EB, Roche TE, Gershwin ME. 1998. Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. Journal of Clinical Investigation 102: 1831-40 25.Jones DEJ, Robe A, Palmer J, Kirby JA. 2006. 20 Adoptive transfer of self-PDC reactive T-cells into naïve mice induces portal tract and bile duct changes characteristic of primary biliary cirrhosis (PBC). Journal of hepatology 44: S10 26.Tanaka A, Borchers AT, Ishibashi H, Ansari AA, Keen CL, Gershwin ME. 2001. Genetic and familial considerations of primary biliary cirrhosis. The American Journal of Gastroenterology 96: 8-15 27.Underhill J, Donaldson P, Bray G, Doherty D, Portmann B, Williams R. 1992. Susceptibility to primary biliary cirrhosis is associated with the HLA-DR8-DQB1*0402 haplotype. Hepatology 16: 1404-8 28.Donaldson PT, Baragiotta A, Heneghan MA, Floreani A, Venturi C, Underhill JA, Jones DEJ, James OFW, Bassendine MF. 2006. HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: A large-scale study. Hepatology 44: 667-74 29.Mullarkey ME, Stevens AM, McDonnell WM, Loubière LS, Brackensick JA, Pang JM, Porter AJ, Galloway DA, Nelson JL. 2005. Human leukocyte antigen class II alleles in Caucasian women with primary biliary cirrhosis. Tissue Antigens 65: 199-205 30.Julianne S, Judy AW, Karen C-D, Chang N, Keith DL, Heathcote EJ. 2002. Human leukocyte antigen Class II associations in serum antimitochondrial antibodies (AMA)-positive and AMA-negative primary biliary cirrhosis. Journal of hepatology 36: 8-13 31.Wassmuth R, Depner F, Danielsson Å, Hultcrantz R, Lööf L, Olson R, Prytz H, Sandberg-Gertzen H, Wallerstedt S, Lindgren S. 2002. HLA class II markers and clinical heterogeneity in Swedish patients with primary biliary cirrhosis. Tissue Antigens 59: 381-7 32.Invernizzi P, Miozzo M, Battezzati PM, Bianchi I, Grati FR, Simoni G, Selmi C, Watnik M, Gershwin M, Podda M. 2004. Frequency of monosomy X in women with primary biliary cirrhosis. The Lancet 363: 533-5 33.Ya-Hui C, William MR, Yoshiyuki U, Gershwin ME. 2008. Animal Models of Primary Biliary Cirrhosis. Clinics in liver disease 12: 333-47 34.Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A. 2008. Liver Autoimmunity Triggered by Microbial Activation of Natural Killer T Cells. Cell host & microbe 3: 304-15 35.Wakabayashi K, Lian Z-X, Leung PSC, Moritoki Y, Tsuneyama K, Kurth MJ, Lam KS, Yoshida K, Yang G-X, Hibi T, Ansari AA, Ridgway WM, Coppel RL, Mackay IR, Gershwin ME. 2008. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 48: 531-40 36.Selmi C, Gershwin ME. 2009. The role of environmental factors in primary biliary cirrhosis. Trends in immunology 30: 415-20 37.Rieger R, Gershwin ME. The X and why of xenobiotics in primary biliary cirrhosis. Journal of Autoimmunity 28: 76-84 38.Reilly EC, Wands JR, Brossay L. 2010. Cytokine dependent and independent iNKT cell activation. Cytokine 51: 227-31 39.Kronenberg M, Gapin L. 2002. The unconventional lifestyle of NKT cells. Nature Reviews Immunology 2: 557-68 40.Ballas ZK, Rasmussen W. 1990. NK1.1+ thymocytes - adult murine CD4-, CD8- thymocytes contain an NK1.1+, CD3+, CD5hi, CD44hi, TCR-V-beta-8+ subset. Journal of Immunology 145: 1039-45 41.Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. 2004. NKT cells: What's in a name? Nature Reviews Immunology 4: 231-7 42.Bendelac A, Savage PB, Teyton L. 2007. The Biology of NKT Cells. Annual Review of Immunology 25: 297-336 43.Stetson DB, Mohrs M, Reinhardt RL, Baron JL, Wang ZE, Gapin L, Kronenberg M, Locksley RM. 2003. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. Journal of Experimental Medicine 198: 1069-76 44.Shimizu H, Matsuguchi T, Fukuda Y, Nakano I, Hayakawa T, Takeuchi O, Akira S, Umemura M, Suda T, Yoshikai Y. 2002. Toll-like receptor 2 contributes to liver injury by Salmonella infection through Fas ligand expression on NKT cells in mice. Gastroenterology 123: 1265-77 45.Askenase PW, Itakura A, Leite-De-Moraes MC, Lisbonne M, Roongapinun S, Goldstein DR, Szczepanik M. 2005. TLR-dependent IL-4 production by invariant Vα14+ Jα 18+ NKT cells to initiate contact sensitivity in vivo. Journal of Immunology 175: 6390-401 46.Brigl M, Brenner MB. 2004. CD1: Antigen presentation and T cell function. pp. 817-90 47.Kronenberg M. 2005. Toward an understanding of NKT cell biology: progress and paradoxes. Annual Review of Immunology 23: 877-900 48.Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M. 1997. CD1d-restricted and TCR-mediated activation of V(α)14 NKT cells by glycosylceramides. Science 278: 1626-9 49.Benlagha K, Weiss A, Beavis A, Teyton L, Bendelac A. 2000. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. Journal of Experimental Medicine 191: 1895-903 50.Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang C-R, Koezuka Y, Kronenberg M. 2000. Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers. The Journal of Experimental Medicine 192: 741-54 51.Smiley ST, Kaplan MH, Grusby MJ. 1997. Immunoglobulin E production in the absence of interleukin-4-secreting CD1-dependent cells. Science 275: 977-9 52.Chen YH, Chiu NM, Mandal M, Wang N, Wang CR. 1997. Impaired NK1+ T cell development and early IL-4 production in CD1-deficient mice. Immunity 6: 459-67 53.Mendiratta SK, Martin WD, Hong S, Boesteanu A, Joyce S, Van Kaer L. 1997. CD1d1 mutant mice are deficient in natural T cells that promptly produce IL-4. Immunity 6: 469-77 54.Gumperz JE, Miyake S, Yamamura T, Brenner MB. 2002. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. Journal of Experimental Medicine 195: 625-36 55.Michel ML, Mendes-da-Cruz D, Keller AC, Lochner M, Schneider E, Dy M, Eberl G, Leite-de-Moraes MC. 2008. Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 105: 19845-50 56.Kinjo Y, Wu D, Kim G, Xing GW, Poles MA, Ho DD, Tsuji M, Kawahara K, Wong CH, Kronenberg M. 2005. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434: 520-5 57.Mattner J, DeBord KL, Ismail N, Goff RD, Cantu Iii C, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A. 2005. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434: 525-9 58.Hegde S, Fox L, Wang X, Gumperz JE. 2010. Autoreactive natural killer T cells: promoting immune protection and immune tolerance through varied interactions with myeloid antigen-presenting cells. Immunology 130: 471-83 59.Beaudoin L, Laloux V, Novak J, Lucas B, Lehuen A. 2002. NKT Cells Inhibit the Onset of Diabetes by Impairing the Development of Pathogenic T Cells Specific for Pancreatic ² Cells. Immunity 17: 725-36 60.Griseri T, Beaudoin L, Novak J, Mars LT, Lepault F, Liblau R, Lehuen A. 2005. Invariant NKT Cells Exacerbate Type 1 Diabetes Induced by CD8 T Cells. The Journal of Immunology 175: 2091-101 61.Lan W, Van Kaer L. 2009. Natural Killer T Cells and Autoimmune Disease. Current Molecular Medicine 9: 4-14 62.Tsuneyama K, Yasoshima M, Harada K, Hiramatsu K, Gershwin ME, Nakanuma Y. 1998. Increased cd1d expression on small bile duct epithelium and epithelioid granuloma in livers in primary biliary cirrhosis. Hepatology 28: 620-3 63.Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He X-S, Koning F, Mikayama T, Van de Water J, Coppel RL, Kaplan M, Gershwin ME. 2002. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 123: 1031-43 64.Chuang Y-H, Lian Z-X, Yang G-X, Shu S-A, Moritoki Y, Ridgway WM, Ansari AA, Kronenberg M, Flavell RA, Gao B, Gershwin ME. 2008. Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 47: 571-80 65.Wu S-J, Yang Y-H, Tsuneyama K, Leung PSC, Illarionov P, Gershwin ME, Chuang Y-H. 2011. Innate immunity and primary biliary cirrhosis: Activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology 53: 915-25 66.Park O, Jeong W-IL, Wang L, Wang H, Lian Z-X, Gershwin ME, Gao B. 2009. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology 49: 1683-94 67.Ishikawa S, Ikejima K, Yamagata H, Aoyama T, Kon K, Arai K, Takeda K, Watanabe S. 2011. CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice. Journal of hepatology 54: 1195-204 68.Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K. 2000. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proceedings of the National Academy of Sciences 97: 5498-503 69.Osman Y, Kawamura T, Naito T, Takeda K, Kaer LV, Okumura K, Abo T. 2000. Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide. European Journal of Immunology 30: 1919-28 70.Wingender G, Krebs P, Beutler B, Kronenberg M. 2010. Antigen-Specific Cytotoxicity by Invariant NKT Cells In Vivo Is CD95/CD178-Dependent and Is Correlated with Antigenic Potency. The Journal of Immunology 185: 2721-9 71.Doisne J-M, Soulard V, Bécourt C, Amniai L, Henrot P, Havenar-Daughton C, Blanchet C, Zitvogel L, Ryffel B, Cavaillon J-M, Marie JC, Couillin I, Benlagha K. 2011. Cutting Edge: Crucial Role of IL-1 and IL-23 in the Innate IL-17 Response of Peripheral Lymph Node NK1.1− Invariant NKT Cells to Bacteria. The Journal of Immunology 186: 662-6 72.Teru Kumagi MA, Yoshiou Ikeda, Yoichi Hiasa. 2010. Infection as a risk factor in the pathogenesis of primary biliary cirrhosis: Pros and cons. Disease Markers 29: 313-21 73.Newton JL, Gibson GJ, Tomlinson M, Wilton K, Jones D. 2006. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology 44: 91-8 74.Okada C, Akbar SMF, Horiike N, Onji M. 2005. Early development of primary biliary cirrhosis in female C57BL/6 mice because of poly I:C administration. Liver International 25: 595-603 75.Mackay IR. 2000. Tolerance and autoimmunity. British Medical Journal 321: 93-6 76.Harada K, Van de Water J, Leung PS, Coppel RL, Ansari A, Nakanuma Y, Gershwin ME. 1997. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: Predominance of the Th1 subset. Hepatology 25: 791-6 77.Nagano T, Yamamoto K, Matsumoto S, Okamoto R, Tagashira M, Ibuki N, Matsumura S, Yabushita K, Okano N, Tsuji T. 1999. Cytokine Profile in the Liver of Primary Biliary Cirrhosis. Journal of Clinical Immunology 19: 422-7 78.Colucci G, Schaffner F, Paronetto F. 1986. In situ characterization of the cell-surface antigens of the mononuclear cell infiltrate and bile duct epithelium in primary biliary cirrhosis. Clinical Immunology and Immunopathology 41: 35-42 79.Kita H, Matsumura S, He X-S, Ansari AA, Lian Z-X, Van de Water J, Coppel RL, Kaplan MM, Gershwin ME. 2002. Quantitative and functional analysis of PDC-E2–specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. The Journal of Clinical Investigation 109: 1231-40 80.Yang G-X, Wu Y, Tsukamoto H, Leung PS, Lian Z-X, Rainbow DB, Hunter KM, Morris GA, Lyons PA, Peterson LB, Wicker LS, Gershwin ME, Ridgway WM. 2011. CD8 T Cells Mediate Direct Biliary Ductule Damage in Nonobese Diabetic Autoimmune Biliary Disease. The Journal of Immunology 186: 1259-67 81.Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V. 2003. NKT Cells Enhance CD4+ and CD8+ T Cell Responses to Soluble Antigen In Vivo through Direct Interaction with Dendritic Cells. The Journal of Immunology 171: 5140-7 82.Van de Water J, Cooper A, Surh CD, Coppel R, Danner D, Ansari A, Dickson R, Gershwin ME. 1989. Detection of Autoantibodies to Recombinant Mitochondrial Proteins in Patients with Primary Biliary Cirrhosis. New England Journal of Medicine 320: 1377-80 83.Miyakawa H, Kikuchi K, Jong-Hon K, Kawaguchi N, Yajima R, Ito Y, Maekubo H. 2001. High sensitivity of a novel ELISA for anti-M2 in primary biliary cirrhosis. Journal of Gastroenterology 36: 33-8 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34562 | - |
dc.description.abstract | 原發性膽道硬化症 (primary biliary cirrhosis;PBC) 為肝臟特異性之自體免疫疾病,特徵為患者肝內膽道上皮細胞遭受破壞致使膽汁鬱積及淋巴浸潤於門脈區,且血清中含高量之抗粒線體自體抗體(AMAs)。iNKT細胞可辨識抗原呈獻細胞上CD1d分子所呈獻之醣脂類抗原,迅速活化後分泌大量細胞激素引起下游免疫反應。本實驗室曾利用xenobiotic (2-OA-BSA) 致敏之PBC小鼠模式,在2-OA-BSA致敏前18~20小時給予α-Galactosylceramide (α-GalCer)活化iNKT細胞,發現小鼠肝臟中CD8+ T細胞數目明顯增加,血清中AMAs效價與肝臟門脈及膽道區域破壞情況上升,且肝臟有纖維化情形。在此,我們進一步研究iNKT細胞之存在與否或是否受外源性醣脂類抗原活化對PBC疾病進程之影響。
在本研究中,我們使用外源性醣脂類抗原,α-GalCer,活化iNKT細胞,觀察2-OA-BSA致敏之PBC小鼠病理變化。結果顯示,小鼠在同時給予α-GalCer及2-OA-BSA致敏後可使其血清中細胞激素迅速上升,且最終可觀察到小鼠之PBC疾病病徵加重,表示當iNKT細胞被活化後,能加速疾病進程;此外,我們亦使用缺乏iNKT細胞之CD1d-/-小鼠與正常小鼠,單獨以2-OA-BSA致敏並觀察PBC進程。結果顯示CD1d-/-小鼠亦可產生門脈區淋巴浸潤及血清中AMAs效價上升等PBC疾病病徵,且相較於同以2-OA-BSA致敏之正常小鼠並無明顯差異。 此結果說明,當缺乏外源性醣脂類物質活化iNKT細胞時,iNKT細胞對於推進PBC疾病進程影響甚小,反之,若給予α-GalCer強力刺激後,活化之iNKT細胞可分泌大量細胞激素,促進肝臟內免疫細胞數目及功能提升,加速淋巴浸潤及膽道破壞,並促使肝臟出現纖維化,加重PBC疾病。 在本研究中,我們使用外源性醣脂類抗原,α-GalCer,活化iNKT細胞,觀察2-OA-BSA致敏之PBC小鼠病理變化。結果顯示,小鼠在同時給予α-GalCer及2-OA-BSA致敏後可使其血清中細胞激素迅速上升,且最終可觀察到小鼠之PBC疾病病徵加重,表示當iNKT細胞被活化後,能加速疾病進程;此外,我們亦使用缺乏iNKT細胞之CD1d-/-小鼠與正常小鼠,單獨以2-OA-BSA致敏並觀察PBC進程。結果顯示CD1d-/-小鼠亦可產生門脈區淋巴浸潤及血清中AMAs效價上升等PBC疾病病徵,且相較於同以2-OA-BSA致敏之正常小鼠並無明顯差異。 此結果說明,當缺乏外源性醣脂類物質活化iNKT細胞時,iNKT細胞對於推進PBC疾病進程影響甚小,反之,若給予α-GalCer強力刺激後,活化之iNKT細胞可分泌大量細胞激素,促進肝臟內免疫細胞數目及功能提升,加速淋巴浸潤及膽道破壞,並促使肝臟出現纖維化,加重PBC疾病。 | zh_TW |
dc.description.abstract | Primary biliary cirrhosis (PBC) is a liver specific autoimmune disease. It is characterized by progressive inflammatory destruction of intrahepatic bile ducts which results in cholestasis and may progress to cirrhosis and liver failure. The most characteristic feature of PBC is the presence of AMAs in the serum. Invariant natural killer (iNKT) cells are restricted to CD1d molecules on antigen-presenting cells and recongized lipids and glycolipids as antigens, such as α-Galactosylceramide (α-GalCer). When NKT cells are stimulated, they are capable to rapidly produce large amounts of cytokines to exert effector functions and immunoregulatory functions. Our previous study using xenobiotic (2-OA-BSA) -induced PBC mouse model demonstrated that activation of iNKT cells by α-GalCer administration prior to 2-OA-BSA immunization could exacerbate the progression of PBC, including increased AMAs production, portal inflammation, increased number of CD8+ T cells in liver, and the formation of liver fibrosis. In this study, we investigated the existence of NKT cells or the administration of exogenous glycolipids to activate iNKT cells in the progression of PBC.
For this purpose, we injected exogenous glycolipids, α-GalCer, and 2-OA-BSA at the same time to mice . After injection of α-GalCer, the elevated serum levels of IFN-γ and IL-4 were revealed, and finally, the exacerbation of PBC pathogenesis were observed. These results suggested that the activation of iNKT cells is important in promoting PBC progression. However, 2-OA-BSA immunized CD1d-/- mice, which lack the receptor required for NKT cell development, also developed the symptom of PBC, such as the lymphocyte infiltration in the portal area in liver, and detectable AMA titers in the serum. Compared to normal mice, there were no significant differences in the severity of disease progression in CD1d-/- mice. In conclusion, our results demonstrated that while the absence of exogenous glycolipids, such as α-GalCer, iNKT cells play a slightly effects in PBC progression, whereas strongly activated by α-GalCer stimulation, iNKT cells could secrete copious amounts of cytokines to elicit the elevated number or function of immune cells in the liver to accelerate liver damage. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T06:15:20Z (GMT). No. of bitstreams: 1 ntu-100-R98424023-1.pdf: 3337633 bytes, checksum: b06c6d01f24f72953d2f8540b11b3add (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 封面
口試委員審定書 碩士論文授權書 致謝 i 摘要 ii Abstract iii Abbreviation v 目錄 vi 圖表目錄 ix 第一章 總論 1 1.1. 肝臟之免疫系統 1 1.2. 原發性膽道硬化症 1 1.2.1. 疾病病理學進程之分級 2 1.2.2. PBC相關之致病因子與病理機制 3 1.2.3. PBC之小鼠動物模式 5 第二章 探討iNKT細胞在原發性膽道硬化症之角色 7 1. 研究背景 7 1.1. 自然殺手T 細胞 7 1.1.1. NKT細胞之分類 7 1.1.2. iNKT細胞之抗原辨識與活化 8 1.1.3. iNKT細胞與自體免疫疾病 9 1.1.4. iNKT細胞與原發性膽道硬化症 10 2. 研究動機與目的 11 3. 材料與方法 12 3.1. 實驗用小鼠 12 3.2. Xenobiotics (2-OA-BSA)引發PBC 小鼠模式之建立 12 3.3. α-galactosylceramide (α-GalCer)之給予 12 3.4. 血清樣品之收集 13 3.5. 小鼠肝臟之灌流與病理切片之製作 13 3.6. 小鼠肝臟單核細胞之純化 13 3.7. 流式細胞儀 (flow cytometry) 分析細胞表面抗原 14 3.8. 以Enzyme linked immunosorbent assay (ELISA)測量血清細胞激素之濃度 15 3.9. 純化以Escherichia coli表現蛋白系統表現之小鼠 PDC-E2 蛋白片段 15 3.10. SDS-PAGE分析mPDC-E2蛋白純度及表現量 15 3.11. 以Enzyme linked immunosorbent assay (ELISA) 測量 PBC小鼠血清中 anti-mPDC-E2 IgG 及 IgM 16 3.12. 小鼠初代肝臟單核細胞之刺激、培養 16 3.13. 以ELISA 測量細胞上清液細胞激素之濃度 16 3.14. 繪圖及統計分析 17 4. 實驗結果 18 4.1. Naïve小鼠給予α-GalCer後,體內iNKT細胞迅速活化,刺激後 2小時內已可偵測出IFN-γ與IL-4之釋放 18 4.2. 不同條件下測試E. coli表現之mPDC-E2可否偵測血清中anti-PDC-E2 IgG與IgM。 18 4.3. 12 週後,給予α-GalCe之PBC小鼠血清AMAs 之效價、肝臟門脈區淋巴浸潤情形均較給予PBS之PBC小鼠嚴重,且有膠原蛋白纖維沉積現象產生 19 4.4. 12 週後,給予α-GalCe之PBC小鼠肝臟中單核細胞總數與組成數目均較給予PBS之PBC小鼠上升 20 4.5. 4 週後,給予α-GalCe之PBC小鼠血清AMAs 之效價及肝臟中單核細胞總數與各種免疫細胞數目均有上升之情形 21 4.6. 4 週後,給予α-GalCer之PBC小鼠肝臟中DCs之百分比與數目皆呈上升情形,且肝臟單核細胞可分泌較高量之IFN-γ 21 4.7. 12 週後,以2-OA-BSA致敏之CD1d-/- 小鼠血清AMAs 之效價、肝臟門脈區淋巴浸潤情形與肝臟中單核細胞總數與組成數目均與CD1d+/- 小鼠無明顯區別 22 4.8. 4週後,給予2-OA-BSA致敏之CD1d-/-小鼠,其肝臟中單核細胞活化情形、DCs呈獻抗原能力及肝臟單核細胞分泌IFN-γ的能力均與WT小鼠無明顯區別 23 5. 結論與討論 25 第三章 圖 31 參考文獻 53 附錄 61 | |
dc.language.iso | zh-TW | |
dc.title | 探討invariant NKT細胞在原發性膽道硬化症之角色 | zh_TW |
dc.title | Study on the Role of Invariant NKT Cells in Primary Biliary Cirrhosis | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陶秘華(Mi-Hua Tao),沈家瑞(Chia-Rui Shen) | |
dc.subject.keyword | 原發性膽道硬化症,iNKT細胞,α-GalCer,2-OA BSA致敏小鼠,CD1d-/- 小鼠, | zh_TW |
dc.subject.keyword | primary biliary cirrhosis,iNKT cells,α-GalCer,2-OA BSA-induced PBC mouse model,CD1d-/- mice, | en |
dc.relation.page | 65 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-07-26 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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