| 研究生: |
翁筠涵 Weng, Yun-Han |
|---|---|
| 論文名稱: |
介白素-20受器一之單株抗體在小鼠氣喘疾病之研究 Study of Anti-IL-20 Receptor 1 Monoclonal Antibody in Asthmatic Murine Model |
| 指導教授: |
張明熙
Chang, Ming-Shi |
| 學位類別: |
碩士 Master |
| 系所名稱: |
醫學院 - 生物化學暨分子生物學研究所 Department of Biochemistry and Molecular Biology |
| 論文出版年: | 2013 |
| 畢業學年度: | 101 |
| 語文別: | 中文 |
| 論文頁數: | 62 |
| 中文關鍵詞: | 細胞激素 、介白素二十受器一 、氣喘 、呼吸道過敏反應 |
| 外文關鍵詞: | Cytokine, IL-20R1, Asthma, Airway hyperresponsiveness |
| 相關次數: | 點閱:83 下載:0 |
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氣喘是一種慢性免疫呼吸道疾病,主要症狀是可逆性的呼吸道狹窄及阻塞。介白素-19是介白素-10家族成員中的一員,由文獻已知介白素-19參與在許多免疫方面的疾病。我們實驗室之前的研究已知氣喘病人血清含有較高量的介白素-19,並且得知介白素-19是透過調控第二型輔助型T細胞作用在氣喘。為了得知介白素-19接受器IL-20R1是否對氣喘有保護作用,我們利用IL-20R1基因剔除小鼠,由鼻腔給予Der P誘導成氣喘動物模式,並與對照組作分析,從結果可以看到IL-20R1基因剔除小鼠在氣喘方面可以降低介白素-13、介白素-19及免疫球蛋白E的產生,同時也能減少免疫細胞浸潤到肺部以及呼吸道過敏反應,從組織切片也能看到IL-20R1基因剔除小鼠的氣管在處理Der P後也不會有增厚的現象。我們同時也利用IL-20R1單株抗體51D以腹腔注射的方式注射到Der P誘導的氣喘小鼠,我們的分析結果發現給予51D的組別,會降低呼吸道過敏反應及血清中介白素-13、介白素-19及免疫球蛋白E的表現量,同時也會降低浸潤至肺部的免疫細胞數目,從免疫組織切片染色結果也的確可以看到51D組別對於氣喘有治療的效果。因此我們實驗結果顯示51D可以降低小鼠氣喘的產生,更可以推論,阻斷介白素-19可能是一個治療氣喘的新方法。
Asthma is a chronic inflammatory disease of the airway. The major symptom of asthma is reversible breathing problems due to airway narrowing and obstruction. IL-19 is a cytokine belonging to the IL-10 family. Our previous studies showed IL-19 was increased in the serum of patients with asthma through the induction of TH2 cytokines. To explore if the antagonist of IL-19 receptor (IL-20 R1) has any protection against asthma, we used Der P to induce chronic asthma animal model in IL-20R1 knock-out mice and analyze the effect of the receptor deficiency on asthma pathogenesis. Our results showed that IL-20R1 deficiency protected against asthma by inhibiting IL-19 , IL-13 , IgE , and blocked infiltration of immune cells in the bronchoalveloar lavage fluids(BALF). IL-20R1 knock-out mice are also protected from asthma by in vivo analysis of airway hyperresponsiveness (AHR) and Hematoxylin /eosin stain. We also found that the anti-IL-20R1 monoclonal antibody, 51D has therapeutic potential for asthma. The 51D antibody was intraperitoneally injected into the Der P sensitized mice. Treatment with 51D reduced airway hyperresponsiveness (AHR) and serum IgE. The numbers of eosinophils in bronchoalveolar lavage fluid and concentrations of IL-13 and IL-19 in serum were also significantly reduced compared to the control. The IL-19-induced in vitro differentiation of TH2 cell from IL-20R1 deficiency mice and IL-19-treated epithelial cell further confirmed our in vivo data. Therefore , Our data demonstrate that anti-IL-20R1 monoclonal antibody, 51D can prevent the development of asthma in a mouse model and conclude that blockade of IL-19 may be a new therapeutic strategy for allergic asthma.
1. J. K. Niles et al., The respiratory pyramid: From symptoms to disease in World Trade Center exposed firefighters. American journal of industrial medicine, (Jun 20, 2013).
2. F. Lichert, [Chronic obstructive lung diseases - "bronchial wall attenuation value" versus standard CT parameter]. RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin 184, 982 (Nov, 2012).
3. T. M. Motawi, H. M. Atta, N. A. Sadik, M. Azzam, The Therapeutic Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Simvastatin in a Rat Model of Liver Fibrosis. Cell biochemistry and biophysics, (Jun 27, 2013).
4. M. Amelink et al., Severe adult-onset asthma: A distinct phenotype. The Journal of allergy and clinical immunology, (Jun 24, 2013).
5. X. Liu et al., Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma. Biochemical and biophysical research communications 386, 181 (Aug 14, 2009).
6. T. T. Le, S. V. Montandon, Efficacy of American College of Allergy Asthma and Immunology symposia and workshops. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 111, 69 (Jul, 2013).
7. B. Donaldson, M. F. Lachowicz, E. A. Stonerook, R. L. Bushardt, Rethinking asthma education: a practical approach to improve treatment outcomes. Jaapa 26, 15 (Jun, 2013).
8. M. Lommatzsch, S. Korn, R. Buhl, J. C. Virchow, Against all odds: anti-IgE for intrinsic asthma? Thorax, (May 24, 2013).
9. I. S. Shin et al., EBM84 attenuates airway inflammation and mucus hypersecretion in an ovalbumin-induced murine model of asthma. International journal of molecular medicine 31, 982 (Apr, 2013).
10. Y. Cao et al., Effect of a peroxynitrite scavenger, a manganese-porphyrin compound on airway remodeling in a murine asthma. Biological & pharmaceutical bulletin 36, 850 (2013).
11. M. L. Burks, E. G. Brooks, V. L. Hill, J. I. Peters, P. R. Wood, Assessing proxy reports: agreement between children with asthma and their caregivers on quality of life. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 111, 14 (Jul, 2013).
12. J. A. Woods, K. L. Nealy, R. W. Barrons, Aclidinium Bromide: An Alternative Long-Acting Inhaled Anticholinergic in the Management of Chronic Obstructive Pulmonary Disease (July/August). The Annals of pharmacotherapy, (Jun 4, 2013).
13. H. Serna, M. Porras, P. Vergara, Mast cell stabilizer ketotifen [4-(1-methyl-4-piperidylidene)-4h-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one fumarate] prevents mucosal mast cell hyperplasia and intestinal dysmotility in experimental Trichinella spiralis inflammation in the rat. The Journal of pharmacology and experimental therapeutics 319, 1104 (Dec, 2006).
14. S. C. Liao et al., IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol 173, 6712 (Dec 1, 2004).
15. C. Hahn et al., Inhibition of the IL-4/IL-13 receptor system prevents allergic sensitization without affecting established allergy in a mouse model for allergic asthma. The Journal of allergy and clinical immunology 111, 1361 (Jun, 2003).
16. A. P. Sampson, IL-5 priming of eosinophil function in asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 31, 513 (Apr, 2001).
17. L. M. Teran, Chemokines and IL-5: major players of eosinophil recruitment in asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 29, 287 (Mar, 1999).
18. J. Corren, Anti-interleukin-13 antibody therapy for asthma: one step closer. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 41, 255 (Feb, 2013).
19. J. L. Ingram, M. Kraft, IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. The Journal of allergy and clinical immunology 130, 829 (Oct, 2012).
20. T. Hirano et al., Persistent elevation of exhaled nitric oxide and modification of corticosteroid therapy in asthma. Respiratory investigation 51, 84 (Jun, 2013).
21. T. A. Jenkins, Perinatal complications and schizophrenia: involvement of the immune system. Frontiers in neuroscience 7, 110 (2013).
22. A. A. Hombach, H. Abken, Targeting two co-operating cytokines efficiently shapes immune responses. Oncoimmunology 2, e23205 (Mar 1, 2013).
23. W. O. Osburn, J. S. Levine, M. A. Chattergoon, D. L. Thomas, A. L. Cox, Anti-inflammatory cytokines, pro-fibrogenic chemokines and persistence of acute HCV infection. Journal of viral hepatitis 20, 404 (Jun, 2013).
24. J. Freedman, P. Iserovich, Pro-inflammatory cytokines in glaucomatous aqueous and encysted Molteno implant blebs, and their relationship to pressure. Investigative ophthalmology & visual science, (Jun 20, 2013).
25. Y. Chen et al., 1,3betaGlucan affects the balance of Th1/Th2 cytokines by promoting secretion of antiinflammatory cytokines in vitro. Molecular medicine reports, (Jun 25, 2013).
26. L. Bossaller, A. Rothe, Monoclonal antibody treatments for rheumatoid arthritis. Expert opinion on biological therapy, (Jun 21, 2013).
27. H. Mizutani et al., Lipopolysaccharide of Aggregatibacter actinomycetemcomitans up-regulates inflammatory cytokines, prostaglandin E synthesis and osteoclast formation in interleukin-1 receptor antagonist-deficient mice. Journal of periodontal research, (Apr 16, 2013).
28. W. J. Jordan et al., Human IL-19 regulates immunity through auto-induction of IL-19 and production of IL-10. European journal of immunology 35, 1576 (May, 2005).
29. H. B. Oral et al., Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26. European journal of immunology 36, 380 (Feb, 2006).
30. E. Omoyinmi et al., Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). PloS one 7, e47673 (2012).
31. Y. C. Liao et al., IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha. J Immunol 169, 4288 (Oct 15, 2002).
32. S. Kunz et al., Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Experimental dermatology 15, 991 (Dec, 2006).
33. R. X. Leng, H. F. Pan, J. H. Tao, D. Q. Ye, IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases. Expert opinion on therapeutic targets 15, 119 (Feb, 2011).
34. S. Commins, J. W. Steinke, L. Borish, The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. The Journal of allergy and clinical immunology 121, 1108 (May, 2008).
35. P. Conti et al., IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26. Immunology letters 88, 171 (Sep 8, 2003).
36. G. Gallagher et al., Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes and immunity 1, 442 (Oct, 2000).
37. L. Dumoutier, C. Leemans, D. Lejeune, S. V. Kotenko, J. C. Renauld, Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 167, 3545 (Oct 1, 2001).
38. K. Liu et al., Mitochondrial toxicity studied with the PBMC of children from the Chinese national pediatric highly active antiretroviral therapy cohort. PloS one 8, e57223 (2013).
39. S. Koks et al., Possible relations between the polymorphisms of the cytokines IL-19, IL-20 and IL-24 and plaque-type psoriasis. Genes and immunity 6, 407 (Aug, 2005).
40. C. H. Hsing et al., Upregulated IL-19 in breast cancer promotes tumor progression and affects clinical outcome. Clinical cancer research : an official journal of the American Association for Cancer Research 18, 713 (Feb 1, 2012).
41. T. Alanara, K. Karstila, T. Moilanen, O. Silvennoinen, P. Isomaki, Expression of IL-10 family cytokines in rheumatoid arthritis: elevated levels of IL-19 in the joints. Scandinavian journal of rheumatology 39, 118 (Mar, 2010).
42. F. Huang et al., Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma. The Journal of allergy and clinical immunology 121, 1415 (Jun, 2008).
43. A. M. Ghaemmaghami, L. Gough, H. F. Sewell, F. Shakib, The proteolytic activity of the major dust mite allergen Der p 1 conditions dendritic cells to produce less interleukin-12: allergen-induced Th2 bias determined at the dendritic cell level. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 32, 1468 (Oct, 2002).
44. R. Torres et al., An intranasal selective antisense oligonucleotide impairs lung cyclooxygenase-2 production and improves inflammation, but worsens airway function, in house dust mite sensitive mice. Respiratory research 9, 72 (2008).
45. A. P. Ligeiro de Oliveira et al., Ovariectomized OVA-Sensitized Mice Display Increased Frequency of CD4(+)Foxp3(+) T Regulatory Cells in the Periphery. PloS one 8, e65674 (2013).
46. M. F. Cao, B. B. Ying, R. E. Xu, S. Y. Zhao, C. B. Li, [Effect of tumor necrosis factor alpha and beta on ionizing radiation-induced apotosis]. Shi yan sheng wu xue bao 35, 198 (Sep, 2002).
47. I. K. Krohn et al., Cultured mast cells from asthmatic patients and controls respond with similar sensitivity to recombinant Der P2 induced, IgE-mediated activation. Scandinavian journal of immunology, (Jun 24, 2013).
48. J. A. Elias, C. G. Lee, IL-13 in asthma. The successful integration of lessons from mice and humans. American journal of respiratory and critical care medicine 183, 957 (Apr 15, 2011).
49. H. J. Gould, B. J. Sutton, IgE in allergy and asthma today. Nature reviews. Immunology 8, 205 (Mar, 2008).
50. Y. Tanizaki et al., [Characteristic of cell components in bronchoalveolar lavage fluid (BALF) in patients with bronchial asthma classified by clinical symptoms]. Arerugi = [Allergy] 39, 75 (Feb, 1990).
51. J. P. Riley et al., Mast cell mediators cause the early allergic bronchoconstriction in guinea pigs in vivo: a model of relevance to asthma. Clin Sci (Lond), (Jun 25, 2013).
52. V. P. Rathod, P. Kapoor, K. K. Pillai, R. Khanam, Assessment of asthma and chronic obstructive pulmonary disorder in relation to reversibility, IgE, eosinophil, and neutrophil count in a University Teaching Hospital in South Delhi, India. Journal of pharmacy & bioallied sciences 2, 337 (Oct, 2010).
53. C. K. Kim, Eosinophil-derived neurotoxin: a novel biomarker for diagnosis and monitoring of asthma. Korean journal of pediatrics 56, 8 (Jan, 2013).
54. Z. Mojtahedi, Possible different serum IL-4 levels across populations: a reason for dissimilar incidence of Th1 and Th2 diseases. Medical hypotheses 78, 776 (Jun, 2012).
55. B. Jayaprakasam et al., Constituents of the anti-asthma herbal formula ASHMI(TM) synergistically inhibit IL-4 and IL-5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro. Journal of integrative medicine 11, 195 (Mar, 2013).
56. P. Deepak, S. Kumar, Jr., D. Kishore, A. Acharya, IL-13 from Th2-type cells suppresses induction of antigen-specific Th1 immunity in a T-cell lymphoma. International immunology 22, 53 (Jan, 2010).
57. P. J. Barnes, Immunology of asthma and chronic obstructive pulmonary disease. Nature reviews. Immunology 8, 183 (Mar, 2008).
58. M. F. Fox, A. Pontier, S. Gurbuxani, D. A. Sipkins, Stem cell factor expression in B cell malignancies is influenced by the niche. Leukemia & lymphoma, (Apr 2, 2013).
59. K. Sebastian, A. Borowski, M. Kuepper, K. Friedrich, Signal transduction around thymic stromal lymphopoietin (TSLP) in atopic asthma. Cell communication and signaling : CCS 6, 5 (2008).
60. P. P. Souza et al., Interleukin-4 and interleukin-13 inhibit the expression of leukemia inhibitory factor and interleukin-11 in fibroblasts. Molecular immunology 49, 601 (Jan, 2012).
61. W. Huo, Z. M. Li, X. M. Zhu, Y. M. Bao, L. J. An, MDA-7/IL-24 suppresses tumor adhesion and invasive potential in hepatocellular carcinoma cell lines. Oncology reports, (May 29, 2013).