臺灣博碩士論文加值系統

氣喘是常見的呼吸道疾病，通常伴隨著慢性肺部發炎、嗜酸性球浸潤及呼吸道受刺激後過度收縮造成呼吸困難等症狀。過度活化之第二型輔助T細胞 (Th2) 及肺部上皮細胞會分泌許多細胞激素及趨化激素使肺部組織發炎反應加劇。其中CCL11 (eotaxin-1) 由受刺激之肺部上皮細胞分泌，引發嗜酸性球聚集至肺部發炎組織中。而克瑞拉細胞(Clara cell)分泌之蛋白質 (CC10; 10 kDa) ，具有抗發炎及免疫調節功能。混合型腺相關病毒 (adeno-associated virus; AAV) 2/9，由AAV2 rep及AAV9 cap基因組成，可以有效地感染肺部上皮細胞，或許可以攜帶具有療效之基因片段應用在氣喘治療。本論文主要探討藉由AAV2/9攜帶雙啟動子 (CMV/U6) 表現CCL11專一之小髮夾RNA (small hairpin RNA; shRNA) 或是直接表現CC10基因片段，來降低氣喘模式小鼠之嗜酸性球浸潤、肺部發炎及Th2反應。氣喘動物模式以重組塵蟎蛋白 (Dermatophagoides pteronyssinus group 2 protein; rDp2) 或是雞卵白蛋白 (Ovalbumin; OVA) 以腹腔注射方式使小鼠過敏，再經由氣管注射方式激發小鼠表現過敏反應，載體病毒在小鼠第一次過敏原激發前三天經由氣管注射打入小鼠肺部。在CCL11 shRNA實驗結果發現，AAV2/9 sh47載體病毒可以有效降低過敏小鼠肺部之呼吸道過度反應、呼吸道阻力、CCL11表現量及嗜酸性球浸潤。肺泡沖洗液 (bronchoalveolar lavage fluid; BALF) 中及經由rDp2刺激之縱隔腔淋巴球所分泌之Th2細胞激素，包括介白素 (IL)-4、IL-5、IL-10及IL-13都明顯下降，膠原性沈積及杯狀細胞過度增生等肺部組織重塑在處理後也都降低；然而血清中rDp2專一之免疫球蛋白 (IgG1及IgE) 及脾臟細胞經rDp2刺激後分泌之Th2細胞激素在不同處理之氣喘小鼠則沒有差異。AAV2/9 CC10載體病毒可恢復原本降低之CC10表現量，並明顯降低OVA引發之過敏小鼠肺部呼吸道過度反應，亦可壓抑肺部CCL11、IL-4、IL-5、IL-6、IL-13表現量、嗜酸性球浸潤及肺部組織重塑。而血清中OVA專一之免疫球蛋白 (IgG1及IgE) 及脾臟細胞經OVA刺激後所分泌之Th2細胞激素，在有CC10載體病毒處理之氣喘小鼠則沒有顯著差異。實驗結果顯示，AAV2/9載體病毒只影響肺部組織周邊的發炎或免疫反應，而不會干擾全身性免疫反應，所以利用AAV2/9 shRNA (由CMV/U6啟動子控制) 針對CCL11進行抑制，可有效地降低肺部嗜酸性球浸潤，而利用AAV2/9 CC10載體病毒穩定表現CC10蛋白質可以達到抗發炎之效果，因此AAV2/9載體病毒可以被應用作為一種新穎的氣喘治療方法。

Asthma is a chronic airway inflammatory disease characterized by eosinophilic infiltration and airway hyperresponsiveness. The over-activated Th2 and lung epithelial cells express many different cytokines and chemokines that mainly contribute to the severity of lung inflammation. CCL11 (eotaxin-1) is secreted by lung epithelial cells and functions as a major chemokine for eosinophil recruitment. Clara cell 10 kDa protein (CC10) that is highly expressed and secreted from airway epithelial cells and exhibits anti-inflammatory and immunomodulatory effects. Pseudotyped adeno-associated virus (AAV) 2/9 vector, composed of AAV2 rep and AAV9 cap genes, can efficiently target lung epithelial cells and might carry gene sequences with therapeutic potential for asthma. This study aimed to determine whether AAV2/9 vector virus carrying the small hairpin RNA targeting CCL11 (expressed by dual CMV/U6 promoter), and carrying CC10 cDNA could reduce eosinophilia, lung inflammation, and Th2 responses in allergen-induced asthma mice. Mice were sensitized by intraperitoneal and challenged by intratracheal injection with recombinant Dermatophagoides pteronyssinus group 2 protein (rDp2) or ovalbumin (OVA). AAV2/9 vector viruses were intratracheally injected three days before the first challenge. In shRNA delivery experiments, the data showed that AAV2/9 sh47 vector virus significantly reduced airway hyperresponsiveness (AHR), airway resistance, CCL11 levels, and eosinophilia in the lungs of sensitized mice. Th2 cytokines, including interleukin (IL)-4, IL-5, IL-10, and IL-13, were significantly reduced in the bronchoalveolar lavage fluid of AAV2/9 sh47 vector virus-treated mice. Th2 cytokine levels were also reduced in rDp2-stimulated mediastinal lymphocytes in treated mice. Lung tissue remodeling, including collagen deposition and goblet cell hyperplasia was alleviated. However, serum levels of rDp2-specific IgG1 and IgE, as well as Th2 cytokine levels in rDp2-stimulated splenocyte culture supernatants, were comparable to the sensitized control group. In CC10 cDNA delivery experiments, the results showed that AAV2/9 CC10 vector virus significantly reduced AHR, the accumulation of CCL11, IL-4, IL-5, IL-6, and IL-13 levels, and eosinophilia in the lungs of sensitized mice. CC10 level in OVA-sensitized mice was rescued with the administration of AAV2/9 CC10 vector virus. Lung tissue remodeling was relieved as in the CCL11 sh47 experiments. The systemic OVA-specific IgG1 and IgE, or Th2 cytokines from OVA stimulated splenocytes were not affected. The results demonstrate that AAV2/9 vector virus relieved local instead of systemic inflammatory responses. Therefore, AAV2/9 shRNA vector virus with CMV/U6 promoter specific to CCL11 efficiently down-regulates eosinophilia, and AAV2/9 CC10 vector virus to ensure sufficient CC10 expression and anti-inflammatory effect in asthmatic mice might be applied as a novel therapeutic approach for asthma.

指導教授同意書
口試委員審定書
國家圖書館博士論文電子檔案上網授權書
長庚大學博士論文著作授權書
致謝 v
中文摘要 vi
Abstract viii
Abbreviations x
Contents xiii
Chapter 1: Introduction 1
1-1 Asthma and dust mite allergens 1
1-2 Rsik genes for asthma 2
1-3 Pathogenesis of asthma 3
1-4 T helper cells and cytokines 4
1-5 Role of eosinophils in asthma 7
1-6 Chemokines in asthma 8
1-7 Clara cell 10 kDa protein (CC10) 9
1-8 Adeno-associated virus (AAV) gene delivery system 10
1-9 Small hairpin RNA (shRNA) 13
1-10 Aims of the study 14
Chapter 2: Materials and Methods 15
2-1 Preparation of recombinant adeno-associated virus (AAV) vector virus 15
2-1-1 Tri-plasmid systems for generating AAV 15
2-1-2 Real-time PCR for viral genome determination (AAV) 16
2-1-3 Long-term virus infection in vivo 16
2-2 Preparation of AAV2/9 CCL11 shRNA and AAV2/9 CC10 vector virus 16
2-2-1 Construction of shRNA expression cassette 16
2-2-2 Testing the efficacy of shRNA targeting CCL11 in vitro 17
2-2-3 Detection of hrGFP fluorescence intensity 18
2-2-4 Construction of CC10 expression cassette 18
2-2-5 Functional assay of recombinant CC10 in vitro 18
2-3 Animal models for AAV2/9 CCL11 shRNA and AAV2/9 CC10 vector virus 19
2-3-1 Animals 19
2-3-2 Preparation of recombinant Dp2 (rDp2) 19
2-3-3 rDp2 sensitization protocol for AAV2/9 CCL11 shRNA vector virus 20
2-3-4 OVA sensitization protocol for AAV2/9 CC10 vector virus 20
2-4 Determination of asthmatic responses 21
2-4-1 AHR and airway resistance 21
2-4-2 Detecting rDp2 or OVA-specific IgG1, IgG2a and IgE antibodies 21
2-4-3 Bronchoalveolar lavage fluid (BALF) 22
2-4-4 Culture lymphocytes from spleens and mediastinal lymph nodes for cytokine profiling 23
2-4-5 The measurement of Th2 and pro-inflammatory cytokines 23
2-4-6 Lung tissues RNA extraction 25
2-4-7 Reverse transcription and real-time PCR 26
2-4-8 Lung tissue staining and immunohistochemistry 26
2-4-9 Statistical analysis 27
Chapter 3: Results 28
3-1 Gene transfer efficiency of recombinant adeno-associated virus (AAV) 28
3-1-1 Gene expression mediated by AAV2/9 control vector virus sustained more than 6 months in vivo 28
3-1-2 The fluorescence intensity of GFP was elevated in AAV2/9 CMV/U6 and CMV promoter-based vector virus-infected cells 28
3-1-3 Reduction of CCL11 level by AAV2/9 shRNA vector viruses in CCL11-NIH 3T3 cells 29
3-1-4 CC10 expressed from AAV2/9 CC10 vector virus infected NIH 3T3 cells reduced IL-6 production in TNF-α-stimulated MLE-12 cells 30
3-2 AAV2/9 vector-derived shRNA knockdown system 30
3-2-1 Significant reduction of eosinophilia and CCL11 level in bronchoalveolar lavage fluid from AAV2/9 sh47 AAV vector virus-treated mice 30
3-2-2 Significant reduction of AHR and airway resistance in AAV2/9 sh47 vector virus-treated mice 32
3-2-3 rDp2-induced tissue remodeling was rescued in the lungs of AAV2/9 sh47 vector virus-treated mice 32
3-2-4 Airway and alveolar cells were specifically infected by AAV2/9 vector virus 33
3-2-5 Reduction of local immune responses in AAV2/9 sh47 vector virus-treated mice 33
3-2-6 Systemic immune responses were not affected in sensitized control and AAV2/9 vector virus-treated mice 34
3-3 AAV2/9 vector-derived gene transfer system 35
3-3-1 AAV2/9 CC10 vector virus rescued CC10 expression in OVA-sensitized mice 35
3-3-2 AAV2/9 CC10 vector virus significantly alleviated AHR in OVA-sensitized mice 35
3-3-3 Significant reduction of eosinophilia in BALF and CCL11 level in lungs of AAV2/9 CC10 vector virus-treated mice 36
3-3-4 Significant reduction of IL-6 and Th2 cytokine gene expression in the lungs of AAV2/9 CC10 vector virus-treated mice 37
3-3-5 Airway tissue remodeling was reduced in the lungs of AAV2/9 CC10 vector virus-treated mice 38
3-3-6 Airway and alveolar cells were specifically infected by AAV2/9 vector virus 38
3-3-7 Systemic immune e responses were not affected after AAV2/9 CC10 vector virus infection 39
Chapter 4: Discussion 40
References 49
Tables 63
Figures 65
Appendix 105

Tables

TABLE 1. List of primer sequences 63
TABLE 2. shRNA sequences specific for CCL11 (eotaxin-1) and luciferase 64

Figures

Fig 1. The construction of different shRNA expression cassettes 65
Fig 2. rDp2 sensitization mouse model 66
Fig 3. OVA sensitization mouse model 67
Fig 4. Long-term gene expression level of hrGFP in lung of AAV2/9 virus-infected mice 68
Fig 5. Increased mean fluorescence intensity (MFI) in CMV/U6, U6 and CMV promoter-based AAV2/9 vector viruses-infected cells 69
Fig 6. Green fluorescence positive cells were detected in CMV/U6, U6 and CMV promoter-based AAV2/9 vector virus-infected cells 70
Fig 7. Reduction of CCL11 levels in CMV/U6, U6 and CMV promoter-based AAV2/9 vector viruses-infected cells 71
Fig 8. AAV2/9 sh47 and sh137 vector viruses suppressed CCL11 protein expression in vitro 72
Fig 9. The medium supernatants from AAV2/9 CC10 vector virus-transduced NIH 3T3 cells suppressed IL-6 production in TNF-α-treated MLE-12 cells 73
Fig 10. AAV2/9 sh47 vector virus reduced total cell and eosinophil numbers in BALF from rDp2-sensitized mice 74
Fig 11. AAV2/9 sh47 vector virus reduced CCL11 expression level in BALF from rDp2-sensitized mice 75
Fig 12. Reduction of airway hyperresponsiveness and airway resistance in AAV2/9 sh47 vector virus-treated mice 76
Fig 13. Reduced eosinophilic infiltration in lung of AAV2/9 sh47 vector virus-treated mice 78
Fig 14. Reduced collagen depositions in lung of AAV2/9 sh47 vector virus-treated mice 80
Fig 15. Reduced goblet cell hyperplasia in lung of AAV2/9 sh47 vector virus-treated mice 82
Fig 16. Airway and alveolar epithelia cells were primary targets for AAV2/9 vector virus 84
Fig 17. AAV2/9 sh47 vector virus reduced Th2 cytokine levels in BALF of rDp2-sensitized mice 85
Fig 18. AAV2/9 sh47 vector virus reduced Th2 cytokine levels in the medium supernatants of lymphocytes from rDp2-stimulated mediastinal lymph nodes in rDp2-sensitized mice 86
Fig 19. No significant difference of serum rDp2-specific IgG1 and IgE levels in sensitized control and AAV2/9 sh47 vector virus-treated mice 87
Fig 20. No significant difference of Th2 cytokine levels in the supernatants of rDp2-stimulated splenocytes among rDp2-sensitized mice 88
Fig 21. AAV2/9 CC10 vector virus enhanced CC10 level in OVA-sensitized mice 89
Fig 22. AAV2/9 CC10 vector virus suppressed AHR in OVA-sensitized mice 90
Fig 23. AAV2/9 CC10 vector virus reduced eosinophil number in BALF from OVA-sensitized mice 91
Fig 24. AAV2/9 CC10 vector virus reduced CCL11 level in lung from OVA-sensitized mice 92
Fig 25. AAV2/9 CC10 vector virus reduced IL-6 and Th2 cytokines levels in lung of OVA-sensitized mice 93
Fig 26. Reduced eosinophilic infiltration in lung of AAV2/9 CC10 vector virus-treated mice 94
Fig 27. Reduced collagen depositions in lung of AAV2/9 CC10 vector virus-treated mice 96
Fig 28. Reduced goblet cell hyperplasia in lung of AAV2/9 CC10 vector virus-treated mice 98
Fig 29. Reduced expression levels of gob5 and muc-5ac in AAV2/9 vector virus-treated mice 100
Fig 30. The airway and alveolar epithelial cells were primary targets for AAV2/9 vector virus 101
Fig 31. No significant difference of serum OVA-specific IgG1 and IgE levels in sensitized control and AAV2/9 vector virus-treated mice 102
Fig 32. No significant difference of Th2 cytokine levels in the supernatants of OVA-stimulated splenocytes among OVA-sensitized mice 103

Acland G.M., Aguirre G.D., Ray J., et al. (2001). Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28, 92-5.
Alexander I.E., Russell D.W., Spence A.M., et al. (1996). Effects of gamma irradiation on the transduction of dividing and nondividing cells in brain and muscle of rats by adeno-associated virus vectors. Hum Gene Ther 7, 841-50.
Atchison R.W., Casto B.C., Hammon W.M. (1966). Electron microscopy of adenovirus-associated virus (AAV) in cell cultures. Virology 29, 353-7.
Auricchio A., O'connor E., Weiner D., et al. (2002). Noninvasive gene transfer to the lung for systemic delivery of therapeutic proteins. J Clin Invest 110, 499-504.
Baekkevold E.S., Yamanaka T., Palframan R.T., et al. (2001). The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J Exp Med 193, 1105-12.
Barnett B.G., Crews C.J., Douglas J.T. (2002). Targeted adenoviral vectors. Biochim Biophys Acta 1575, 1-14.
Bell C.L., Vandenberghe L.H., Bell P., et al. (2011). The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice. J Clin Invest 121, 2427-2435.
Berns K.I., Linden R.M. (1995). The cryptic life style of adeno-associated virus. Bioessays 17, 237-45.
Bosnjak B., Stelzmueller B., Erb K.J., et al. (2011). Treatment of allergic asthma: modulation of Th2 cells and their responses. Respir Res 12, 114.
Brantly M.L., Spencer L.T., Humphries M., et al. (2006). Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther 17, 1177-86.
Brightling C.E., Bradding P., Symon F.A., et al. (2002). Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 346, 1699-705.
Bruselle G.G., Kips J.C., Peleman R.A., et al. (1997). Role of IFN-gamma in the inhibition of the allergic airway inflammation caused by IL-12. Am J Respir Cell Mol Biol 17, 767-71.
Brusselle G., Kips J., Joos G., et al. (1995). Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am J Respir Cell Mol Biol 12, 254-9.
Campbell E.M., Kunkel S.L., Strieter R.M., et al. (1998). Temporal role of chemokines in a murine model of cockroach allergen-induced airway hyperreactivity and eosinophilia. J Immunol 161, 7047-7053.
Campbell H.D., Tucker W.Q., Hort Y., et al. (1987). Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin 5). Proc Natl Acad Sci U S A 84, 6629-33.
Cantero-Recasens G., Fandos C., Rubio-Moscardo F., et al. (2010). The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet 19, 111-21.
Chang Y.C., Hsieh K.H. (1989). The study of house dust mites in Taiwan. Ann Allergy 62, 101-6.
Chen C.C., Sun C.P., Ma H.I., et al. (2009). Comparative study of anti-hepatitis B virus RNA interference by double-stranded adeno-associated virus serotypes 7, 8, and 9. Mol Ther 17, 352-359.
Chen J., Lam S., Pilon A., et al. (2008). Higher levels of the anti-inflammatory protein CC10 are associated with improvement in bronchial dysplasia and sputum cytometric assessment in individuals at high risk for lung cancer. Clin Cancer Res 14, 1590-7.
Chen L.C., Zhang Z., Myers A.C., et al. (2001). Cutting edge: altered pulmonary eosinophilic inflammation in mice deficient for Clara cell secretory 10-kDa protein. J Immunol 167, 3025-8.
Chiba Y., Kurotani R., Kusakabe T., et al. (2006). Uteroglobin-related protein 1 expression suppresses allergic airway inflammation in mice. Am J Respir Crit Care Med 173, 958-64.
Chirmule N., Propert K., Magosin S., et al. (1999). Immune responses to adenovirus and adeno-associated virus in humans. Gene Ther 6, 1574-83.
Christine C.W., Starr P.A., Larson P.S., et al. (2009). Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73, 1662-9.
Colucci R., Fornai M., Tuccori M., et al. (2007). Tolerability Profiles of Leukotriene Receptor Antagonists and Long-Acting beta(2)-Adrenoceptor Agonists in Combination with Inhaled Corticosteroids for Treatment of Asthma: A Review. J Asthma 44, 411-22.
Cottard V., Mulleman D., Bouille P., et al. (2000). Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis. Gene Ther 7, 1930-9.
Coyle A.J., Le Gros G., Bertrand C., et al. (1995). Interleukin-4 is required for the induction of lung Th2 mucosal immunity. Am J Respir Cell Mol Biol 13, 54-9.
Denli A.M., Tops B.B., Plasterk R.H., et al. (2004). Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231-5.
Di Pasquale G., Chiorini J.A. (2006). AAV transcytosis through barrier epithelia and endothelium. Mol Ther 13, 506-516.
Douglas J.T. (2007). Adenoviral vectors for gene therapy. Mol Biotechnol 36, 71-80.
Dow S.W., Elmslie R.E., Fradkin L.G., et al. (1999a). Intravenous cytokine gene delivery by lipid-DNA complexes controls the growth of established lung metastases. Hum Gene Ther 10, 2961-72.
Dow S.W., Schwarze J., Heath T.D., et al. (1999b). Systemic and local interferon gamma gene delivery to the lungs for treatment of allergen-induced airway hyperresponsiveness in mice. Hum Gene Ther 10, 1905-14.
Engelhardt J.F., Zepeda M., Cohn J.A., et al. (1994). Expression of the cystic fibrosis gene in adult human lung. J Clin Invest 93, 737-49.
Erles K., Sebokova P., Schlehofer J.R. (1999). Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J Med Virol 59, 406-11.
Finkelman F.D., Katona I.M., Urban J.F., Jr., et al. (1988). IL-4 is required to generate and sustain in vivo IgE responses. J Immunol 141, 2335-41.
Fire A., Xu S., Montgomery M.K., et al. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-11.
Flood-Page P., Menzies-Gow A., Phipps S., et al. (2003). Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 112, 1029-36.
Flory J.H., Sleiman P.M., Christie J.D., et al. (2009). 17q12-21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. J Allergy Clin Immunol 124, 605-7.
Flotte T.R. (2001). Recombinant adeno-associated virus vectors for cystic fibrosis gene therapy. Curr Opin Mol Ther 3, 497-502.
Flotte T.R., Trapnell B.C., Humphries M., et al. (2011). Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results. Hum Gene Ther 22, 1239-47.
Foster P.S., Hogan S.P., Ramsay A.J., et al. (1996). Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med 183, 195-201.
Fujisawa T., Kato Y., Nagase H., et al. (2000). Chemokines induce eosinophil degranulation through CCR-3. J Allergy Clin Immunol 106, 507-13.
Galanter J., Choudhry S., Eng C., et al. (2008). ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am J Respir Crit Care Med 177, 1194-200.
Gao G., Vandenberghe L.H., Alvira M.R., et al. (2004). Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol 78, 6381-8.
Gao G.P., Lu F., Sanmiguel J.C., et al. (2002). Rep/Cap gene amplification and high-yield production of AAV in an A549 cell line expressing Rep/Cap. Mol Ther 5, 644-9.
Gauvreau G.M., Boulet L.P., Cockcroft D.W., et al. (2008). Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med 177, 952-958.
Gavett S.H., O'hearn D.J., Karp C.L., et al. (1997). Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice. Am J Physiol 272, L253-61.
Gavett S.H., O'hearn D.J., Li X., et al. (1995). Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med 182, 1527-36.
Gerblich A.A., Salik H., Schuyler M.R. (1991). Dynamic T-cell changes in peripheral blood and bronchoalveolar lavage after antigen bronchoprovocation in asthmatics. Am Rev Respir Dis 143, 533-7.
Gleich G.J., Adolphson C.R. (1986). The eosinophilic leukocyte: structure and function. Adv Immunol 39, 177-253.
Goncalves M.A. (2005). Adeno-associated virus: from defective virus to effective vector. Virol J 2, 43.
Gonzalez R., Yang Y.H., Griffin C., et al. (2005). Freshly isolated rat alveolar type I cells, type II cells, and cultured type II cells have distinct molecular phenotypes. Am J Physiol Lung Cell Mol Physiol 288, L179-189.
Gonzalo J.A., Jia G.Q., Aguirre V., et al. (1996). Mouse Eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response. Immunity 4, 1-14.
Gonzalo J.A., Lloyd C.M., Wen D., et al. (1998). The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness. J Exp Med 188, 157-167.
Gregory R.I., Chendrimada T.P., Cooch N., et al. (2005). Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123, 631-40.
Grunig G., Warnock M., Wakil A.E., et al. (1998). Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261-3.
Halbert C.L., Allen J.M., Miller A.D. (2001). Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors. J Virol 75, 6615-24.
Halbert C.L., Rutledge E.A., Allen J.M., et al. (2000). Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J Virol 74, 1524-1532.
Hamelmann E., Gelfand E.W. (2001). IL-5-induced airway eosinophilia--the key to asthma? Immunol Rev 179, 182-91.
Hammad H., De Heer H.J., Soullie T., et al. (2003). Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1. J Immunol 171, 3936-40.
Harrod K.S., Mounday A.D., Stripp B.R., et al. (1998). Clara cell secretory protein decreases lung inflammation after acute virus infection. Am J Physiol 275, L924-30.
Hassani Z., Francois J.C., Alfama G., et al. (2007). A hybrid CMV-H1 construct improves efficiency of PEI-delivered shRNA in the mouse brain. Nucleic Acids Res 35, e65.
Hayashida S., Harrod K.S., Whitsett J.A. (2000). Regulation and function of CCSP during pulmonary Pseudomonas aeruginosa infection in vivo. Am J Physiol Lung Cell Mol Physiol 279, L452-9.
Heilbronn R., Weger S. (2010). Viral vectors for gene transfer: current status of gene therapeutics. Handb Exp Pharmacol, 143-170.
Hirota T., Harada M., Sakashita M., et al. (2008). Genetic polymorphism regulating ORM1-like 3 (Saccharomyces cerevisiae) expression is associated with childhood atopic asthma in a Japanese population. J Allergy Clin Immunol 121, 769-70.
Hofstra C.L., Van Ark I., Hofman G., et al. (1998). Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels. J Immunol 161, 5054-60.
Hogan S.P., Foster P.S., Tan X., et al. (1998a). Mucosal IL-12 gene delivery inhibits allergic airways disease and restores local antiviral immunity. Eur J Immunol 28, 413-23.
Hogan S.P., Mould A.W., Young J.M., et al. (1998b). Cellular and molecular regulation of eosinophil trafficking to the lung. Immunol Cell Biol 76, 454-60.
Hsieh C.S., Macatonia S.E., Tripp C.S., et al. (1993). Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547-9.
Hsu C.Y., Leu S.J., Chiang B.L., et al. (2010). Cytokine gene-modulated dendritic cells protect against allergic airway inflammation by inducing IL-10(+)IFN-gamma(+)CD4(+) T cells. Gene Ther 17, 1011-21.
Huang H.Y., Lee C.C., Chiang B.L. (2008). Small interfering RNA against interleukin-5 decreases airway eosinophilia and hyper-responsiveness. Gene Ther 15, 660-667.
Huang H.Y., Lee C.C., Chiang B.L. (2009). Short hairpin RNAs against eotaxin or interleukin-5 decrease airway eosinophilia and hyper-responsiveness in a murine model of asthma. J Gene Med 11, 112-118.
Hung C.H., Chen L.C., Zhang Z., et al. (2004). Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 114, 664-70.
Jacoby D.B., Costello R.M., Fryer A.D. (2001). Eosinophil recruitment to the airway nerves. J Allergy Clin Immunol 107, 211-8.
Jacoby D.B., Gleich G.J., Fryer A.D. (1993). Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. J Clin Invest 91, 1314-8.
Jiang H., Pierce G.F., Ozelo M.C., et al. (2006). Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol Ther 14, 452-5.
Jirapongsananuruk O., Leung D.Y. (1997). Clinical applications of cytokines: new directions in the therapy of atopic diseases. Ann Allergy Asthma Immunol 79, 5-16; quiz 19-20.
Joachim R.A., Sagach V., Quarcoo D., et al. (2007). Effect of stress on eotaxin and expression of adhesion molecules in a murine model of allergic airway inflammation. J Neuroimmunol 182, 55-62.
Johnston C.J., Mango G.W., Finkelstein J.N., et al. (1997). Altered pulmonary response to hyperoxia in Clara cell secretory protein deficient mice. Am J Respir Cell Mol Biol 17, 147-55.
Justice J.P., Borchers M.T., Crosby J.R., et al. (2003). Ablation of eosinophils leads to a reduction of allergen-induced pulmonary pathology. Am J Physiol Lung Cell Mol Physiol 284, L169-78.
Kam K.L., Hsieh K.H. (1994). Comparison of three in vitro assays for serum IgE with skin testing in asthmatic children. Ann Allergy 73, 329-36.
Kay A.B., Klion A.D. (2004). Anti-interleukin-5 therapy for asthma and hypereosinophilic syndrome. Immunol Allergy Clin North Am 24, 645-66, vii.
Kita H. (1996). The eosinophil: a cytokine-producing cell? J Allergy Clin Immunol 97, 889-92.
Kotin R.M., Siniscalco M., Samulski R.J., et al. (1990). Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A 87, 2211-5.
Lacoste J.Y., Bousquet J., Chanez P., et al. (1993). Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J Allergy Clin Immunol 92, 537-48.
Lambrecht B.N., De Veerman M., Coyle A.J., et al. (2000). Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J Clin Invest 106, 551-9.
Lee Y.C., Zhang Z., Mukherjee A.B. (2006). Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett 580, 4515-20.
Lee Y.L., Ye Y.L., Yu C.I., et al. (2001). Construction of single-chain interleukin-12 DNA plasmid to treat airway hyperresponsiveness in an animal model of asthma. Hum Gene Ther 12, 2065-79.
Leigh M.W., Kylander J.E., Yankaskas J.R., et al. (1995). Cell proliferation in bronchial epithelium and submucosal glands of cystic fibrosis patients. Am J Respir Cell Mol Biol 12, 605-612.
Lewis B.P., Burge C.B., Bartel D.P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15-20.
Lewitt P.A., Rezai A.R., Leehey M.A., et al. (2011). AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 10, 309-19.
Li G., Liu Z., Zhong N., et al. (2006). Therapeutic effects of DNA vaccine on allergen-induced allergic airway inflammation in mouse model. Cell Mol Immunol 3, 379-384.
Limberis M.P., Vandenberghe L.H., Zhang L., et al. (2009). Transduction efficiencies of novel AAV vectors in mouse airway epithelium in vivo and human ciliated airway epithelium in vitro. Mol Ther 17, 294-301.
Limberis M.P., Wilson J.M. (2006). Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered. Proc Natl Acad Sci U S A 103, 12993-12998.
Liu Q., Muruve D.A. (2003). Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther 10, 935-40.
Liu W., Li Z., Luo Q., et al. (2011). The elevated expression of osteopontin and vascular endothelial growth factor in sinonasal inverted papilloma and its relationship with clinical severity. Am J Rhinol Allergy 25, 313-7.
Liu Z., Lu X., Zhang X.H., et al. (2009). Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 64, 149-57.
Locksley R.M. (1994). Th2 cells: help for helminths. J Exp Med 179, 1405-7.
Lode H.N., Dreier T., Xiang R., et al. (1998). Gene therapy with a single chain interleukin 12 fusion protein induces T cell-dependent protective immunity in a syngeneic model of murine neuroblastoma. Proc Natl Acad Sci U S A 95, 2475-80.
Lund E., Guttinger S., Calado A., et al. (2004). Nuclear export of microRNA precursors. Science 303, 95-8.
Lusby E., Fife K.H., Berns K.I. (1980). Nucleotide sequence of the inverted terminal repetition in adeno-associated virus DNA. J Virol 34, 402-9.
Macpherson J.C., Comhair S.A., Erzurum S.C., et al. (2001). Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J Immunol 166, 5763-72.
Madden K.B., Urban J.F., Jr., Ziltener H.J., et al. (1991). Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J Immunol 147, 1387-91.
Mallol J., Aguirre V., Aguilar P., et al. (2007). Changes in the prevalence of asthma in Chilean school age children between 1994 and 2002. Rev Med Chil 135, 580-6.
Mandal A.K., Zhang Z., Ray R., et al. (2004). Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 199, 1317-30.
Manno C.S., Chew A.J., Hutchison S., et al. (2003). AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101, 2963-72.
Marks W.J., Jr., Bartus R.T., Siffert J., et al. (2010). Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol 9, 1164-72.
Martinez F.D., Stern D.A., Wright A.L., et al. (1995). Association of interleukin-2 and interferon-gamma production by blood mononuclear cells in infancy with parental allergy skin tests and with subsequent development of atopy. J Allergy Clin Immunol 96, 652-60.
Mccarty D.M., Fu H., Monahan P.E., et al. (2003). Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther 10, 2112-8.
Mcfadden E.R., Jr., Gilbert I.A. (1992). Asthma. N Engl J Med 327, 1928-37.
Mease P.J., Hobbs K., Chalmers A., et al. (2009). Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study. Ann Rheum Dis 68, 1247-54.
Mease P.J., Wei N., Fudman E.J., et al. (2010). Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 Study. J Rheumatol 37, 692-703.
Metcalfe D.D., Baram D., Mekori Y.A. (1997). Mast cells. Physiol Rev 77, 1033-79.
Moffatt M.F., Kabesch M., Liang L., et al. (2007). Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470-3.
Mori S., Wang L., Takeuchi T., et al. (2004). Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology 330, 375-83.
Moschos S.A., Frick M., Taylor B., et al. (2011). Uptake, efficacy, and systemic distribution of naked, inhaled short interfering RNA (siRNA) and locked nucleic acid (LNA) antisense. Mol Ther 19, 2163-2168.
Moss R.B., Milla C., Colombo J., et al. (2007). Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther 18, 726-32.
Mueller C., Braag S.A., Martino A.T., et al. (2009). The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr-/- -dependent allergy mouse model. Gene Ther 16, 172-183.
Mukherjee A.K. (2007). Correlation between the phospholipids domains of the target cell membrane and the extent of Naja kaouthia PLA(2)-induced membrane damage: evidence of distinct catalytic and cytotoxic sites in PLA(2) molecules. Biochimica et biophysica acta 1770, 187-95.
Muruve D.A. (2004). The innate immune response to adenovirus vectors. Hum Gene Ther 15, 1157-66.
Natt F. (2007). siRNAs in drug discovery: target validation and beyond. Curr Opin Mol Ther 9, 242-7.
O'byrne P.M., Inman M.D., Adelroth E. (2004). Reassessing the Th2 cytokine basis of asthma. Trends Pharmacol Sci 25, 244-8.
Ohl L., Henning G., Krautwald S., et al. (2003). Cooperating mechanisms of CXCR5 and CCR7 in development and organization of secondary lymphoid organs. J Exp Med 197, 1199-204.
Ou-Yang H.F., Hu X.B., Ti X.Y., et al. (2009). Suppression of allergic airway inflammation in a mouse model by Der p2 recombined BCG. Immunology 128, e343-352.
Overbergh L., Valckx D., Waer M., et al. (1999). Quantification of murine cytokine mRNAs using real time quantitative reverse transcriptase PCR. Cytokine 11, 305-12.
Platts-Mills T.A., Thomas W.R., Aalberse R.C., et al. (1992). Dust mite allergens and asthma: report of a second international workshop. J Allergy Clin Immunol 89, 1046-60.
Postma D.S., Bleecker E.R., Amelung P.J., et al. (1995). Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 333, 894-900.
Rabinowitz J.E., Rolling F., Li C., et al. (2002). Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 76, 791-801.
Rohde V., Erles K., Sattler H.P., et al. (1999). Detection of adeno-associated virus in human semen: does viral infection play a role in the pathogenesis of male infertility? Fertil Steril 72, 814-6.
Rose J.A., Berns K.I., Hoggan M.D., et al. (1969). Evidence for a single-stranded adenovirus-associated virus genome: formation of a DNA density hybrid on release of viral DNA. Proc Natl Acad Sci U S A 64, 863-9.
Rosenwasser L.J., Klemm D.J., Dresback J.K., et al. (1995). Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 25 Suppl 2, 74-8; discussion 95-6.
Rothenberg M.E. (1998). Eosinophilia. N Engl J Med 338, 1592-600.
Rothenberg M.E., Maclean J.A., Pearlman E., et al. (1997). Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia. J Exp Med 185, 785-790.
Rutledge E.A., Halbert C.L., Russell D.W. (1998). Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol 72, 309-19.
Samulski R.J., Zhu X., Xiao X., et al. (1991). Targeted integration of adeno-associated virus (AAV) into human chromosome 19. Embo J 10, 3941-50.
Sanderson C.J. (1990). The biological role of interleukin 5. Int J Cell Cloning 8 Suppl 1, 147-53; discussion 153-4.
Schmidt M., Voutetakis A., Afione S., et al. (2008). Adeno-associated virus type 12 (AAV12): a novel AAV serotype with sialic acid- and heparan sulfate proteoglycan-independent transduction activity. J Virol 82, 1399-406.
Schuh J.M., Blease K., Kunkel S.L., et al. (2003). Chemokines and cytokines: axis and allies in asthma and allergy. Cytokine Growth Factor Rev 14, 503-10.
Seder R.A., Paul W.E., Davis M.M., et al. (1992). The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med 176, 1091-8.
Singh G., Katyal S.L. (1997). Clara cells and Clara cell 10 kD protein (CC10). Am J Respir Cell Mol Biol 17, 141-3.
Smit J.J., Lukacs N.W. (2006). A closer look at chemokines and their role in asthmatic responses. Eur J Pharmacol 533, 277-88.
Song S., Embury J., Laipis P.J., et al. (2001a). Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Ther 8, 1299-306.
Song S., Embury J., Laipis P.J., et al. (2001b). Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Ther 8, 1299-1306.
Starosta V., Ratjen F., Rietschel E., et al. (2006). Anti-inflammatory cytokines in cystic fibrosis lung disease. Eur Respir J 28, 581-7.
Stripp B.R., Lund J., Mango G.W., et al. (1996). Clara cell secretory protein: a determinant of PCB bioaccumulation in mammals. Am J Physiol 271, L656-64.
Su J., Zhu Z., Xiong F., et al. (2008). Hybrid cytomegalovirus-U6 promoter-based plasmid vectors improve efficiency of RNA interference in zebrafish. Mar Biotechnol 10, 511-517.
Thomas W.R., Smith W.A., Hales B.J., et al. (2002). Characterization and immunobiology of house dust mite allergens. Int Arch Allergy Immunol 129, 1-18.
Tomari Y., Matranga C., Haley B., et al. (2004). A protein sensor for siRNA asymmetry. Science 306, 1377-80.
Tomkinson A., Duez C., Cieslewicz G., et al. (2001). Eotaxin-1-deficient mice develop airway eosinophilia and airway hyperresponsiveness. Int Arch Allergy Immunol 126, 119-125.
Tsai J.J., Liu Y.H., Shen H.D., et al. (2002). Prevention of Der p2-induced allergic airway inflammation by Mycobacterium-bacillus Calmette Guerin. J Microbiol Immunol Infect 35, 152-158.
Tsai J.J., Wu H.H., Shen H.D., et al. (1998). Sensitization to Blomia tropicalis among asthmatic patients in Taiwan. Int Arch Allergy Immunol 115, 144-9.
Turner H., Kinet J.P. (1999). Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature 402, B24-30.
Van Oosterhout A.J., Ladenius A.R., Savelkoul H.F., et al. (1993). Effect of anti-IL-5 and IL-5 on airway hyperreactivity and eosinophils in guinea pigs. Am Rev Respir Dis 147, 548-52.
Venge P., Bystrom J., Carlson M., et al. (1999). Eosinophil cationic protein (ECP): molecular and biological properties and the use of ECP as a marker of eosinophil activation in disease. Clin Exp Allergy 29, 1172-86.
Wang C.C., Fu C.L., Yang Y.H., et al. (2006). Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma. Gene Ther. 13, 1414-1421.
Wang H., Long X.B., Cao P.P., et al. (2010). Clara cell 10-kD protein suppresses chitinase 3-like 1 expression associated with eosinophilic chronic rhinosinusitis. Am J Respir Crit Care Med 181, 908-16.
Wang S.Y., Yang M., Xu X.P., et al. (2008). Intranasal delivery of T-bet modulates the profile of helper T cell immune responses in experimental asthma. J Investig Allergol Clin Immunol 18, 357-365.
Wardlaw A.J., Dunnette S., Gleich G.J., et al. (1988). Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am Rev Respir Dis 137, 62-9.
Warrington K.H., Jr., Herzog R.W. (2006). Treatment of human disease by adeno-associated viral gene transfer. Hum Genet 119, 571-603.
Weghofer M., Thomas W.R., Pittner G., et al. (2005). Comparison of purified Dermatophagoides pteronyssinus allergens and extract by two-dimensional immunoblotting and quantitative immunoglobulin E inhibitions. Clin Exp Allergy 35, 1384-91.
Weller P.F. (1994). Eosinophils: structure and functions. Curr Opin Immunol 6, 85-90.
Weller P.F., Lim K., Wan H.C., et al. (1996). Role of the eosinophil in allergic reactions. Eur Respir J Suppl 22, 109s-115s.
Wills-Karp M. (1999). Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol 17, 255-81.
Wills-Karp M. (2004). Interleukin-13 in asthma pathogenesis. Immunol Rev 202, 175-90.
Wills-Karp M., Luyimbazi J., Xu X., et al. (1998). Interleukin-13: central mediator of allergic asthma. Science 282, 2258-61.
Wu C.A., Peluso J.J., Shanley J.D., et al. (2008). Murine cytomegalovirus influences Foxj1 expression, ciliogenesis, and mucus plugging in mice with allergic airway disease. Am J Pathol 172, 714-24.
Xiao X., Li J., Samulski R.J. (1996). Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol 70, 8098-108.
Xue Y.Q., Ma B.F., Zhao L.R., et al. (2010). AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease. Gene Ther 17, 83-94.
Yang C.J., Liu Y.K., Liu C.L., et al. (2009). Inhibition of Acidic Mammalian Chitinase by RNA Interference Suppresses Ovalbumin-Sensitized Allergic Asthma. Hum Gene Ther 20, 1597-1606.
Yang R., Tan X., Thomas A.M., et al. (2007). Alanine-glutamine dipeptide (AGD) inhibits expression of inflammation-related genes in hemorrhagic shock. JPEN J Parenter Enteral Nutr 31, 32-6.
Yang Y., Loy J., Ryseck R.P., et al. (1998). Antigen-induced eosinophilic lung inflammation develops in mice deficient in chemokine eotaxin. Blood 92, 3912-23.
Yang Y., Zhang Z., Mukherjee A.B., et al. (2004). Increased susceptibility of mice lacking Clara cell 10-kDa protein to lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen in cigarette smoke. J Biol Chem 279, 29336-40.
Ye X., Rivera V.M., Zoltick P., et al. (1999). Regulated delivery of therapeutic proteins after in vivo somatic cell gene transfer. Science 283, 88-91.
Zabner J., Seiler M., Walters R., et al. (2000). Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer. J Virol 74, 3852-8.
Zavorotinskaya T., Tomkinson A., Murphy J.E. (2003). Treatment of experimental asthma by long-term gene therapy directed against IL-4 and IL-13. Mol Ther 7, 155-162.
Zhang Z., Kundu G.C., Yuan C.J., et al. (1997). Severe fibronectin-deposit renal glomerular disease in mice lacking uteroglobin. Science 276, 1408-12.
Zhang Z., Kundu G.C., Zheng F., et al. (2000). Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches. Ann N Y Acad Sci 923, 210-33.
Zheng F., Kundu G.C., Zhang Z., et al. (1999). Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nat Med 5, 1018-25.
Zimmermann N., Hershey G.K., Foster P.S., et al. (2003). Chemokines in asthma: cooperative interaction between chemokines and IL-13. J Allergy Clin Immunol 111, 227-42; quiz 243.