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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 廖泰慶(Tai-Ching Liao),林大盛(Dah-Sheng Lin),嚴仲陽(Jeffrey J. Y. Yen) | |
| dc.contributor.author | Yu-Ling Lan | en |
| dc.contributor.author | 藍玉靈 | zh_TW |
| dc.date.accessioned | 2021-06-13T06:40:49Z | - |
| dc.date.available | 2017-07-30 | |
| dc.date.copyright | 2011-07-27 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-07-25 | |
| dc.identifier.citation | 1. Krensky AM, Clayberger C. Biology and clinical relevance of granulysin. Tissue Antigens. 2009; 73 (3): 193-198.
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Science. 2004; 304 (5667): 104-107. 30. Shultz LD, Lyons BL, Burzenski LM, et al. Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells. J Immunol. 2005; 174 (10): 6477-6489. 31. Ito R, Katano I, Kawai K, et al. Highly Sensitive Model for Xenogenic GVHD Using Severe Immunodeficient NOG Mice. Transplantation. 2009; 87 (11): 1654-1658 32. Liu Y, Hangoc G, Campbell TB, et al. Identification of parameters required for efficient lentiviral vector transduction and engraftment of human cord blood CD34+ NOD/SCID-repopulating cells. Exp Hematol. 2008; 36 (8): 947-956. 33. Jeon MS, Lim HJ, Yi TG, et al. Xenoreactivity of human clonal mesenchymal stem cells in a major histocompatibility complex-matched allogeneic graft-versus-host disease mouse model. Cell Immunol. 2010; 261 (1): 57-63. 34. Pearson T, Greiner DL, Shultz LD. Creation of “Humanized” Mice to Study Human Immunity: John Wiley & Sons, Inc.; 2001. 35. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007; 7 (2): 118-130. 36. Gimeno R, Weijer K, Voordouw A, et al. Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2-/- γc-/- mice: functional inactivation of p53 in developing T cells. Blood. 2004; 104 (13): 3886-3893. 37. Pearson T, Shultz LD, Miller D, et al. Non-obese diabetic–recombination activating gene-1 (NOD–Rag 1 null) interleukin (IL)-2 receptor common gamma chain (IL 2 rγnull) null mice: a radioresistant model for human lymphohaematopoietic engraftment. Clin Exp Immunol. 2008; 154 (2): 270-284. 38. Rivas MN, Hazzan M, Weatherly K, Gaudray F, Salmon I, Braun MY. NK Cell Regulation of CD4 T Cell-Mediated Graft-versus-Host Disease. J Immunol. 2010; 184 (12): 6790-6798. 39. King MA, Covassin L, Brehm MA, et al. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol. 2009; 157 (1): 104-118. 40. Pino S, Brehm MA, Covassin-Barberis L, et al. Development of Novel Major Histocompatibility Complex Class I and Class II-Deficient NOD-SCID IL2R Gamma Chain Knockout Mice for Modeling Human Xenogeneic Graft-Versus-Host Disease. In: Proetzel G, Wiles MV, eds. Mouse Models for Drug Discovery. Vol 602: Humana Press; 2010: 105-117. 41. Yahata T, Ando K, Nakamura Y, et al. Functional Human T Lymphocyte Development from Cord Blood CD34+ Cells in Nonobese Diabetic/Shi-scid, IL-2 Receptor γNull Mice. J Immunol. 2002; 169 (1): 204-209. 42. Jaatinen T, Laine J. Isolation of Mononuclear Cells from Human Cord Blood by Ficoll-Paque Density Gradient: John Wiley & Sons, Inc.; 2007. 43. Martinez-Chantar ML, Corrales FJ, Martinez-Cruz A, et al. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J. 2002; 16 (10): 1292-1294. 44. Murphy WJ, Welniak LA, Taub DD, et al. Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Clin Invest. 1998; 102 (9):17421748. 45. Yang YG, Dey BR, Sergio JJ, Pearson DA, Sykes M. Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Inves. 1998; 102 (12): 2126-2135. 46. Inoue M, Senju S, Hirata S, Irie A, Baba H, Nishimura Y. An in vivo model of priming of antigen-specific human CTL by Mo-DC in NOD/Shi-scid IL2rγnull (NOG) mice. Immunol Lett. 2009; 126 (1-2): 67-72. 47. Notta F, Doulatov S, Dick JE. Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgc-null recipients. Blood. 2010; 115 (18): 3704-3707. 48. Choi B, Chun E, Kim M, et al. Human T cell development in the liver of humanized NOD/SCID/IL-2Rγnull (NSG) mice generated by intrahepatic injection of CD34+ human (h) cord blood (CB) cells. Clin Immunol. 2011; 139 (3): 321-335. 49. Martin-Padura I, Agliano A, Marighetti P, Porretti L, Bertolini F. Sex-related efficiency in NSG mouse engraftment. Blood. 2010; 116 (14): 2616-2617. 50. Das R, Komorowski R, Hessner MJ, et al. Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses. Blood. 2010; 115 (25): 5249-5258. 51. Schmook T, Kraft J, Benninghoff B, et al. Treatment of cutaneous chronic graft-versus-host disease with topical pimecrolimus. Bone Marrow Transplant. 2005; 36 (1): 87-88. 52. Chung WH, Hung SI, Hong HS, et al. Medical genetics: A marker for Stevens-Johnson syndrome. Nature. 2004; 428 (6982): 486-486. 53. Thong BY-H. Update on the Management of Antibiotic Allergy. Allergy Asthma Immunol Res. 2010; 2 (2): 77-86. 54. Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol. 23 (2): 171-181. 55. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006; 16 (4): 297-306. 56. Tassaneeyakul W, Jantararoungtong T, Chen P, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics. 2009; 19 (9): 704-709. 57. Hippen KL, Harker-Murray P, Porter SB, et al. Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells. Blood. 2008; 112 (7): 2847-2857. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/35096 | - |
| dc.description.abstract | 儘管捐贈者的毒殺型T淋巴細胞 (CTLs) 與自然殺手細胞 (NK cells) 在引起移植物抗宿主症 (graft-versus-host disease) 的角色被確立，然而對於導致病患皮膚、黏膜細胞壞死脫落及多重器官衰竭的細胞毒性蛋白的身分仍不清楚。顆粒溶解素(granulysin) 則是在最近研究中指出可能引致移植物抗宿主症的一種細胞毒性蛋白。由於小鼠的基因組中並沒有顆粒溶解素的基因，所以傳統的小鼠模式並不適合用來進一步研究顆粒溶解素與移植物抗宿主症的關係。本篇論文中，我們報告利用人類臍帶血單核細胞植入至經放射線處理過的免疫系統嚴重缺陷小鼠( NOD/Lt-scid IL2rγ null mice; NSG mice)，在免疫系統擬人化小鼠中建立異體移植物抗宿主症動物模式 (HIS-X-GVHD)。在此HIS-X-GVHD模式中，我們觀察到小鼠產生體重下降、皮膚及黏膜細胞壞死等移植物抗宿主症之症狀，並於小鼠的肝、脾、肺、腎、皮膚及血清中發現高量人類來源之免疫細胞及人類的細胞激素。免疫化學染色可見人類CD45+、CD8+之免疫細胞及顆粒溶解素在小鼠肝、脾、肺、腎及皮膚組織中高度表現。最重要的是，血清中顆粒溶解素的濃度與異種移植物抗宿主症之嚴重程度有顯著相關。
綜合以上結果顯示，此移植物抗宿主症之免疫系統擬人化之小鼠模式可提供作為顆粒溶解素作用機制的研究，並提供作為新穎治療藥物臨床前評估的新工具。 | zh_TW |
| dc.description.abstract | Although the involvement of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK cells) in the pathogenesis of graft-versus-host-disease (GVHD) have been well established, the cytotoxic proteins that are responsible for the skin and organ toxicity remains to be clarified. Recently a mechanism involving a cytotoxic protein, granulysin, was proposed. However, study on the functional role of granulysin in GVHD has been hampered by lack of appropriate mouse GVHD model due to the absence of granulysin gene in the mouse genome. Here, we developed a humanized immune system (HIS) mouse model with xenogenic-GVHD based on the intravenous injection of human umbilical cord blood mononuclear cells (UCBMCs) into sublethally irradiated NOD/Lt-scid IL2rγ null (NSG) mice. The HIS-X-GVHD mouse model exhibited human cells engraftment and human cytokine production with lymphocytic infiltration in the liver, spleen, lung, kidney and skin. Futhermore, immunohistochemistry demonstrated that the infiltrative lymphocytes in various organs were predominantly human CD45+ and CD8+ cells. Importantly, we found that granulysin was highly expressed in the liver, spleen, lung, kidney and skin. Besides, Serum granulysin levels were positively correlated with severity of GVHD. The HIS mouse model with X-GVHD provides the opportunity to investigate in vivo mechanisms of the regulation of granulysin, as well as to test the novel therapeutics for treatment of GVHD. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T06:40:49Z (GMT). No. of bitstreams: 1 ntu-100-R98629007-1.pdf: 3460648 bytes, checksum: f115572dd06d6308a4866d694f1a80d5 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 審定書 i
誌謝 ii 摘要 iii Abstract iv Abbreviation vi Contents vii List of figures x List of tables xii Chapter 1. Introduction 1 1.1 The multiple aspects of granulysin 1 1.2 Graft-versus-host disease (GVHD) 2 1.3 Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) 4 1.4 The relevance among granulysin, GVHD and SJS-TEN 4 1.5 Pathophysiology of human acute GVHD 6 1.6 TH1 and TH2 cytokines 7 1.7 Humanized immune system mice (HIS mice) 8 1.8 The benefits of modeling human disease in NSG mice 9 Chapter 2. Material & Method 11 2.1 Animal husrandrey 11 2.2 Whole body irradiation of mice 11 2.3 Flow cytometry analysis 12 2.4 UCBMC isolation and transplantation 12 2.5 Complete blood counting and blood chemistry 13 2.6 Enzyme-linked immunosorbent assay (ELISA) of granulysin 14 2.7 Histology and immunohistochemistry 15 2.8 Pathologic scoring and grading of GVHD 16 2.9 Western blot analysis 17 2.10 Cytokine cytometric beads array analysis 18 2.11 Statistical analysis 18 Chapter 3. Results 20 3.1 The lymphohematopoietic phenotype of the NSG mice 20 3.2 Irradiation sensitivity of NSG mice 21 3.3 Development of HIS-X-GVHD model 21 3.4 Hematological reconstitution in HIS-X-GVHD mice 22 3.5 Multi-organ infiltration of human immune cells 22 3.6 Histopathological-based scoring system for HIS-X-GVHD 24 3.7 Correlation between serum granulysin protein levels and pathological severity 25 3.8 Impaired hepatic and renal function in HIS-X-GVHD mice26 3.9 Expression of human granulysin in HIS-X-GVHD mice 27 3.10 Human cytokine profiling in HIS-X-GVHD mice 27 Chapter 4. Discussion 28 4.1 The advantages of using NOD-scid IL2rγnull (NSG) mice to establish HIS-X-GVHD mouse model 28 4.2 Efficiency of human cells engraftment in NSG mice 29 4.3 Gender effect in human cells engraftment 30 4.4 Correlation between serum granulysin and the severity of HIS-X-GVHD 30 4.5 The utilization of HIS-X-GVHD mouse model 31 4.6 TH1 cytokine in HIS-X-GVHD mouse model 32 4.7 The long-life-span of HIS-X-GVHD mouse model 32 References 57 List of Figures Figure 1. Hematological characterization and spleen cell populations in 8-and-24- wks-old Balb/c, NOD-SCID and NSG mice 34 Figure 2 The HIS mice model showed the signs of X-GVHD 36 Figure 3. Hematological analysis of HIS-X-GVHD 38 Figure 4. Histopathology of liver of NSG mouse with HIS-X-GVHD compared with control 39 Figure 5. Histopathology of spleen of NSG mouse with HIS-X-GVHD compared with control 40 Figure 6. Histopathology of lung of NSG mouse with HIS-X-GVHD compared with control 41 Figure 7. Histopathology of kidney of NSG mouse with HIS-X-GVHD compared with control 42 Figure 8. Histopathology of skin of NSG mouse with HIS-X-GVHD compared with control 43 Figure 9. The amount of granulysin positively proportional to the histopathological severity findings 44 Figure 10. The amount of granulysin positively proportional to the histopathological severity findings 45 Figure 11. The amount of granulysin positively proportional to the histopathological severity findings 46 Figure 12. The amount of granulysin positively proportional to the histopathological severity findings 47 Figure 13. The amount of granulysin positively proportional to the histopathological severity findings 48 Figure 14. Concentration of serum granulysin is correlated with the severity of HIS-X-GVHD 49 Figure 15. Abnormalities of hepatic and renal function tests of HIS-X-GVHD mice 50 Figure 16. Western blot analysis of granulysin expression 52 Figure 17. Human IFN-γexpression in the serum of HIS-X-GVHD grade IV mice 53 List of Table Table 1. Radiation sensitivity of NSG mice 54 Table 2. Histopathologic score and grade of graft-versus-host-disease 55 Table 3. The scores and grades of GVHD and serum granulysin concentration of the mice analyzed 56 | |
| dc.language.iso | en | |
| dc.title | 建立表現顆粒溶解素之移植物抗宿主症之免疫系統擬人化小鼠 | zh_TW |
| dc.title | Expression of Granulysin in Humanized Mouse Model
System of Xenogeneic Graft-versus-Host-Disease | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.advisor-orcid | ,林大盛(dsl@ntu.edu.tw) | |
| dc.contributor.oralexamcommittee | 陳垣崇(Yuan-Tsong Chen),蕭樑材(Liang -Tsai Hsiao) | |
| dc.subject.keyword | 移植物抗宿主症,毒殺型T淋巴細胞,自然殺手細胞,顆粒溶解素,免疫系統擬人化小鼠,臍帶血來源之單核細胞, | zh_TW |
| dc.subject.keyword | graft-versus-host-disease,cytotoxic T lymphocytes,NK cells,granulysin,humanized immune system mouse model,umbilical cord blood mononuclear cells., | en |
| dc.relation.page | 65 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-07-25 | |
| dc.contributor.author-college | 獸醫專業學院 | zh_TW |
| dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
| 顯示於系所單位： | 獸醫學系 | |
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