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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 江伯倫(Bor-Luen Chiang) | |
| dc.contributor.author | Kun-Hui Lu | en |
| dc.contributor.author | 呂昆輝 | zh_TW |
| dc.date.accessioned | 2021-06-15T00:58:39Z | - |
| dc.date.available | 2008-09-11 | |
| dc.date.copyright | 2008-09-11 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-08-01 | |
| dc.identifier.citation | 1. Huggins, J.L. and H.I. Brunner, Targeting B cells in the treatment of childhood-onset systemic lupus erythematosus. J Pediatr, 2006. 148(5): p. 571-3.
2. Rahman, A. and D.A. Isenberg, Systemic lupus erythematosus. N Engl J Med, 2008. 358(9): p. 929-39. 3. Johnson, A.E., et al., The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum, 1995. 38(4): p. 551-8. 4. Buyon, J.P., et al., The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med, 2005. 142(12 Pt 1): p. 953-62. 5. Inui, A., et al., Estrogen receptor expression by peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Clin Rheumatol, 2007. 26(10): p. 1675-8. 6. Suzuki, T., et al., Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol, 1995. 99(2): p. 251-5. 7. Kammer, G.M. and N. Mishra, Systemic lupus erythematosus in the elderly. Rheum Dis Clin North Am, 2000. 26(3): p. 475-92. 8. Ballestar, E., M. Esteller, and B.C. Richardson, The epigenetic face of systemic lupus erythematosus. J Immunol, 2006. 176(12): p. 7143-7. 9. Wakeland, E.K., et al., Delineating the genetic basis of systemic lupus erythematosus. Immunity, 2001. 15(3): p. 397-408. 10. Walport, M.J., Complement and systemic lupus erythematosus. Arthritis Res, 2002. 4 Suppl 3: p. S279-93. 11. Walport, M.J., C.M. Black, and J.R. Batchelor, The immunogenetics of SLE. Clin Rheum Dis, 1982. 8(1): p. 3-21. 12. Morel, L., et al., Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc Natl Acad Sci U S A, 2000. 97(12): p. 6670-5. 13. Strickland, F.M. and B.C. Richardson, Epigenetics in human autoimmunity. Epigenetics in autoimmunity - DNA methylation in systemic lupus erythematosus and beyond. Autoimmunity, 2008. 41(4): p. 278-86. 14. Harley, J.B., et al., The curiously suspicious: a role for Epstein-Barr virus in lupus. Lupus, 2006. 15(11): p. 768-77. 15. James, J.A., et al., An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest, 1997. 100(12): p. 3019-26. 16. Borchers, A.T., C.L. Keen, and M.E. Gershwin, Drug-induced lupus. Ann N Y Acad Sci, 2007. 1108: p. 166-82. 17. Millard, T.P., J.L. Hawk, and J.M. McGregor, Photosensitivity in lupus. Lupus, 2000. 9(1): p. 3-10. 18. Tan, E.M., et al., The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum, 1982. 25(11): p. 1271-7. 19. Isenberg, D.A., et al., Fifty years of anti-ds DNA antibodies: are we approaching journey's end? Rheumatology (Oxford), 2007. 46(7): p. 1052-6. 20. ter Borg, E.J., et al., Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum, 1990. 33(5): p. 634-43. 21. Bootsma, H., et al., The predictive value of fluctuations in IgM and IgG class anti-dsDNA antibodies for relapses in systemic lupus erythematosus. A prospective long-term observation. Ann Rheum Dis, 1997. 56(11): p. 661-6. 22. Grammer, A.C. and P.E. Lipsky, B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther, 2003. 5 Suppl 4: p. S22-7. 23. Hayakawa, K., et al., The 'Ly-1 B' cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med, 1983. 157(1): p. 202-18. 24. Nisitani, S., T. Sakiyama, and T. Honjo, Involvement of IL-10 in induction of autoimmune hemolytic anemia in anti-erythrocyte Ig transgenic mice. Int Immunol, 1998. 10(8): p. 1039-47. 25. Duan, B. and L. Morel, Role of B-1a cells in autoimmunity. Autoimmun Rev, 2006. 5(6): p. 403-8. 26. Murakami, M., et al., Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice. Nature, 1992. 357(6373): p. 77-80. 27. Murakami, M., et al., Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells. Int Immunol, 1995. 7(5): p. 877-82. 28. Ishida, H., et al., Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med, 1994. 179(1): p. 305-10. 29. Berland, R. and H.H. Wortis, Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol, 2002. 20: p. 253-300. 30. Xiao, C., et al., MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell, 2007. 131(1): p. 146-59. 31. Herzenberg, L.A., et al., The Ly-1 B cell lineage. Immunol Rev, 1986. 93: p. 81-102. 32. Peng, B., et al., Growth inhibition of malignant CD5+B (B-1) cells by antisense IL-10 oligonucleotide. Leuk Res, 1995. 19(3): p. 159-67. 33. Yen Chong, S., et al., Cell cycle effects of IL-10 on malignant B-1 cells. Genes Immun, 2001. 2(5): p. 239-47. 34. Li, M.O. and R.A. Flavell, Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity, 2008. 28(4): p. 468-76. 35. Jou, S.T., et al., Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol, 2002. 22(24): p. 8580-91. 36. Okkenhaug, K., et al., Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science, 2002. 297(5583): p. 1031-4. 37. Okkenhaug, K. and B. Vanhaesebroeck, PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol, 2003. 3(4): p. 317-30. 38. Okkenhaug, K. and B. Vanhaesebroeck, PI3K-signalling in B- and T-cells: insights from gene-targeted mice. Biochem Soc Trans, 2003. 31(Pt 1): p. 270-4. 39. Marshall, A.J., et al., Regulation of B-cell activation and differentiation by the phosphatidylinositol 3-kinase and phospholipase Cgamma pathway. Immunol Rev, 2000. 176: p. 30-46. 40. Curnock, A.P. and K.A. Knox, LY294002-mediated inhibition of phosphatidylinositol 3-kinase activity triggers growth inhibition and apoptosis in CD40-triggered Ramos-Burkitt lymphoma B cells. Cell Immunol, 1998. 187(2): p. 77-87. 41. Padmore, L., G.K. Radda, and K.A. Knox, Wortmannin-mediated inhibition of phosphatidylinositol 3-kinase activity triggers apoptosis in normal and neoplastic B lymphocytes which are in cell cycle. Int Immunol, 1996. 8(4): p. 585-94. 42. Miller, D.G., M.A. Adam, and A.D. Miller, Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol, 1990. 10(8): p. 4239-42. 43. Ramezani, A. and R.G. Hawley, Overview of the HIV-1 Lentiviral Vector System. Curr Protoc Mol Biol, 2002. Chapter 16: p. Unit 16 21. 44. Yamashita, M. and M. Emerman, Retroviral infection of non-dividing cells: old and new perspectives. Virology, 2006. 344(1): p. 88-93. 45. Steward, M.W., F.E. Katz, and N.J. West, The role of low affinity antibody in immune complex disease. The quantity of anti-DNA antibodies in NZB/W F1 hybrid mice. Clin Exp Immunol, 1975. 21(1): p. 121-30. 46. Helyer, B.J. and J.B. Howie, Renal disease associated with positive lupus erythematosus tests in a cross-bred strain of mice. Nature, 1963. 197: p. 197. 47. Davis, H.E., J.R. Morgan, and M.L. Yarmush, Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes. Biophys Chem, 2002. 97(2-3): p. 159-72. 48. Seitz, B., et al., Retroviral vector-mediated gene transfer into keratocytes: in vitro effects of polybrene and protamine sulfate. Graefes Arch Clin Exp Ophthalmol, 1998. 236(8): p. 602-12. 49. Perez, E.C., et al., B-1 lymphocytes increase metastatic behavior of melanoma cells through the extracellular signal-regulated kinase pathway. Cancer Sci, 2008. 99(5): p. 920-8. 50. Chiorazzi, N., S.L. Allen, and M. Ferrarini, Clinical and laboratory parameters that define clinically relevant B-CLL subgroups. Curr Top Microbiol Immunol, 2005. 294: p. 109-33. 51. Hardy, R.R., B-1 B cells: development, selection, natural autoantibody and leukemia. Curr Opin Immunol, 2006. 18(5): p. 547-55. 52. Raveche, E.S., et al., Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood, 2007. 109(12): p. 5079-86. 53. Greenwald, R.J., et al., E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia. Blood, 2004. 103(4): p. 1475-84. 54. Peterson, L.K., I. Tsunoda, and R.S. Fujinami, Role of CD5+ B-1 cells in EAE pathogenesis. Autoimmunity, 2008. 41(5): p. 353-62. 55. Mannik, M., et al., Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus. J Rheumatol, 2003. 30(7): p. 1495-504. 56. Fillatreau, S., D. Gray, and S.M. Anderton, Not always the bad guys: B cells as regulators of autoimmune pathology. Nat Rev Immunol, 2008. 8(5): p. 391-7. 57. O'Garra, A., et al., Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. Int Immunol, 1990. 2(9): p. 821-32. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/42301 | - |
| dc.description.abstract | 系統性紅斑狼瘡(systemic lupus erythematosus)是多因性的自體免疫疾病，致病因子間的交互作用複雜且並不明確。不同的免疫細胞與分子在疾病發展過程中，扮演了多樣且分歧的角色。在之前的研究中研究者發現，將B-1細胞以低滲透壓環境或移除10型介白質(IL-10)的方式，從系統性紅斑狼瘡的模式小鼠身上移除後，疾病將會得到緩解，換言之，移除B-1細胞是有潛力的治療概念。然而，臨床上於病患腹腔產生低張環境或移除10型介白質都將導致大規模的周邊組織破壞與副作用，因此，移除B-1細胞的概念需要更有應用價值的方式。另一系列的研究發現，在磷酸肌醇-3-激酶(phosphoinositide 3 kinase, PI3K)的催化性次單元中，p110δ具有在免疫細胞中表現的專一性。從胚胎基因體中剔除(knock out) p110δ或是置入p110δ的顯性功能缺陷變異體(dominant negative)，都將阻礙B細胞的發育，其中，B-1細胞幾近完全消失。由此可以推想p110δ與B-1細胞的存在有重要的關聯。因此，我們將透過基因特異性的方法，抑制p110δ的表現，試圖移除B-1細胞，進一步治療系統性紅斑狼瘡。首先，我們發現在成體中，抑制磷酸肌醇-3-激酶的功能仍能顯著降低B-1細胞的數量。接著，我們以兩種反轉錄病毒攜帶我們設計的小干擾型核醣核酸(siRNAs)，發現它們能顯著抑制p110δ的表現。之後，我們將抑制磷酸肌醇-3-激酶的抑制劑與由病毒攜帶的小干擾型核醣核酸，投入系統性紅斑狼瘡的模式小鼠進行活體治療。目前，我們發現抑制劑LY294002與低量給予的小干擾型核醣核酸，會對抗雙股去氧核醣核酸的自體抗體(anti-dsDNA auto-antibody)的發生，產生顯著的抑制作用或抑制趨勢。由於自體抗體的產生是系統性紅斑狼瘡的重要病理指標，因此，針對磷酸肌醇-3-激酶或更精確地針對p110δ的基因特異性調控將有潛力成為系統性紅斑狼瘡的應用療法。此外，證明磷酸肌醇-3-激酶與B-1細胞族群的維持相關也提供嶄新的研究方向，嘗試治療其他與B-1細胞相關的疾病。 | zh_TW |
| dc.description.abstract | Systemic lupus erythematosus is an autoimmune disease caused by multiple but elusive pathogenic factors. Different immune components play diverse roles in varied stages and aspects. Previous studies upon SLE-prone murine models demonstrated that the removal of B-1 cells by either hypotonic shock or IL-10 deprivation was beneficial to relieve the disease flare. However, these experimental approaches possess ominous potentials to cause immense damages and side-effects and thus are not considerable for further clinical indications. Knock-out or dominant-negative model against p110δ, a leukocyte-specific catalytic subunit of PI3Ks, are proved to be able to abrogate the maturation of B cell lineages, especially the marginal zone B cell and B-1 cell populations. Thus, we look for a more specific approach to remove B-1 cells through targeting p110δ. At first, we proved that PI3Ks are not only important for the development of B-1 cells but still essential for the maintenance of their population after birth. We then designed shRNAs carried by either retroviral or lentiviral systems and validated that several among them can sufficiently knock down the expression of p110δ. We introduced either pan-specific inhibitors against all PI3Ks or p110δ-targeting shRNAs into an SLE-prone animal model, NZB/W F1 mice, for therapeutic purposes. We found salutary effects in our preliminary data. One inhibitor, LY294002, significantly delayed the accumulation of anti-dsDNA IgG auto-antibody. shRNAs delivered by low dose of lentivirus exhibited certain potential to retard the rising of anti-dsDNA IgG auto-antibody, too. Our findings are not only promising for developing treatments against SLE. Knowing that PI3Ks are critical for the maintenance of B-1 cell populations also shed light on dealing with other diseases associated with B-1 cells, such as certain melanoma, lymphoma, or leukemia. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T00:58:39Z (GMT). No. of bitstreams: 1 ntu-97-R95449003-1.pdf: 1557048 bytes, checksum: 678ef19f4982bed533f71de1e6ad2571 (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 致謝……………………………………………………………………ii
中文摘要………………………………………………………………………………1 Abstract……………………………………………………………………………… 2 Contents……………………………………………………………………………… 3 Introduction……………………………………………………………………………6 Systemic Lupus Erythematosus and B-1 cells..……………………………………7 More therapeutic ways to deplete B-1 cells for SLE therapy………………………8 p110δ and B-1 cells...………………………………………………………………9 PI3Ks for the maintenance of B-1 population after birth…………………………11 RNAi strategy……………………………………………………………………11 Pathological indicators…………………………………………………………..12 Study summary……………………………………………………………………13 Materials and Methods……………………………………………………………….14 1. cells and in vitro culture system……………………………………………15 1.1 cell lines…………………………………………………………………15 1.2 primary cells……………………………………………………………15 1.3 culture systems…………………………………………………………16 2. Wortmannin & LY294002 treatments in Balb/c……………………………16 3. shRNA design and delivery systems…………………………………………...17 3.1 target sequences searching……………...………………………………..18 3.2 vectors and cloning………………………………………………………18 3.3 retroviral system………………………………………………………...19 3.4 lentiviral system…………………………………………………………19 3.5 infection efficiency…………………………………………………….20 3.6 Infectious unit (I.F.U.)…………………………………………………..20 3.7 in vitro shut-down efficiency by real-time PCR…………………………21 4. monitoring of pathological indicators…………………………………….21 4.1 sampling & weighting…………………………………………………21 4.2 body weight…………………………………………………………….22 4.4 ELISA for anti-ssDNA / anti-dsDNA auto-antibodies……………22 4.5 nephrites…………………………………………………………………22 4.6 survival rate……………………………………………………………23 5. treatments in murine SLE model……………………………………………23 6. statistics & graphing……………………………………………………………24 Results …………………………………………………………………………………25 1. Wortmannin & LY294002 treatments in Balb/c………………………………26 2. shRNA design and delivery systems………………………………………27 2.1 target sequences searching………………………………………27 2.2 vectors and cloning……………………………………………………28 2.3 retroviral system…………………………………………………………28 2.4 lentiviral system…………………………………………………………29 2.5 infection efficiency………………………………………………………30 2.6 in vitro shut-down efficiency by real-time PCR…………………………..31 3. treatments and responses in murine SLE model………………………………33 3.1 anti-DNA auto-antobody.………………………………………………….33 3.2 body weight……………………………………………………………….34 3.3 survival rate….……………………………………………………………34 Discussion……………………………………………………………………………35 Figures & Tables………………………………………………………………………40 References…………………………………………………………………………68 Appendix…………………………………………………………………………77 | |
| dc.language.iso | en | |
| dc.subject | B-1細胞 | zh_TW |
| dc.subject | 小干擾型核醣核酸 | zh_TW |
| dc.subject | 磷酸肌醇-3-激酶 | zh_TW |
| dc.subject | 系統性紅斑狼瘡 | zh_TW |
| dc.subject | phosphoinositide 3 kinase | en |
| dc.subject | lentivirus | en |
| dc.subject | NZB/W F1 | en |
| dc.subject | RNAi | en |
| dc.subject | PI3Ks | en |
| dc.subject | B-1 cell | en |
| dc.subject | SLE | en |
| dc.subject | Systemic Lupus Erythematosus | en |
| dc.title | 全身性紅斑狼瘡之可能療法—
藉由抑制p110δ訊息傳遞分子干擾B-1細胞之功能 | zh_TW |
| dc.title | Targeting signaling molecule, p110δ, to interfere B-1 functions for potential therapy against murine systemic lupus erythematosus | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 司徒惠康(Huey-Kang Sytwu),繆希椿(Shi-Chuan Maiw) | |
| dc.subject.keyword | 系統性紅斑狼瘡,B-1細胞,磷酸肌醇-3-激酶,小干擾型核醣核酸, | zh_TW |
| dc.subject.keyword | Systemic Lupus Erythematosus,SLE,B-1 cell,phosphoinositide 3 kinase,PI3Ks,RNAi,NZB/W F1,lentivirus, | en |
| dc.relation.page | 86 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-08-02 | |
| 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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