Immunologic Research

, 37:147

Flt3-ligand plasmid prevents the development of pathophysiological features of chronic asthma in a mouse model

  • Jehad H. Edwan
  • Devendra K. Agrawal


Airway inflammation and remodeling are primary characteristics of long-standing asthma. A balance between the TH1/TH2 cytokines regulates the accumulation and activation of inflammatory cells, including mast cells and eosinophils. Recently, we demonstrated that pUMVC3-hFLex, an active plasmid, mammalian expression vector for the secretion of Flt3-L, reversed established airway hyperresponsiveness (AHR) in a murine model of acute allergic airway inflammation. The present experiments were undertaken to examine the effect of pUMVC3-hFLex in a chronic model of allergic airway inflammation that was established in Balb/c mice by sensitization and challenge with ovalbumin (OVA). pUMVC3-hFLex or the control plasmid, pUMVC3, were administered by injection into the muscle interior tibialis. Treatment with pUMVC3-hFLex completely reversed established AHR (p<0.05), and this effect continued even after several exposures to the allergen (p<0.05). pUMVC3-hFLex treatment prevented the development of goblet cell hyperplasia and subepithelial fibrosis, and significantly reduced serum levels of IL-4 and IL-5, and increased serum IL-10 levels (p<0.05) with no effect on serum IL-13. Serum IgE or serum total and anti-OVA IgG1 and IgG2a levels did not change. Total BALF cellularity and BALF IL-5 levels were reduced (p<0.05), but there was no significant effect on BALF IL-10 and IL-13. These results suggest that pUMVC3-hFLex treatment can prevent the development of airway remodeling and maintain airway protection in chronic experimental asthma model, and might provide a novel approach for treating chronic asthma.

Key Words

Allergy Asthma Flt3-L Mouse model of asthma pUMVC3-hFLex plasmid TH1/TH2 cells 


  1. 1.
    Vignola AM, Kips J, Bousquet J: Tissue remodeling as a feature of persistent asthma. J Allergy Clin Immunol 2000;105:1041.PubMedCrossRefGoogle Scholar
  2. 2.
    Beato M, Herrlich P, Schutz G: Steroid hormone receptors: many actors in search of a plot. Cell 1995;83:851.PubMedCrossRefGoogle Scholar
  3. 3.
    Barnes PJ, Pedersen S, Busse WW: Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998;157:S1.Google Scholar
  4. 4.
    Covar RA, Leung DY, McCormick D, Steelman J, Zeitler P, Spahn JD: Risk factors associated with glucocorticoid-induced adverse effects in children with severe asthma. J Allergy Clin Immunol 2000;106:651.PubMedCrossRefGoogle Scholar
  5. 5.
    Adcock IM: Steroid resistance in asthma. Molecular mechanisms. Am J Respir Crit Care Med 1996;154:S58-S61.PubMedGoogle Scholar
  6. 6.
    Agrawal DK, Hopfenspirger MT, Chavez J, Talmadge JE: Flt3 ligand: a novel cytokine prevents allergic asthma in a mouse model. Int Immunopharmacol 2001;1:2081.PubMedCrossRefGoogle Scholar
  7. 7.
    Edwan JH, Perry G, Talmadge JE, Agrawal DK: Flt-3 ligand reverses late allergic response and airway hyper-responsiveness in a mouse model of allergic inflammation. J Immunol 2004;172:5016.PubMedGoogle Scholar
  8. 8.
    Lyman SD, James L, Johnson L, et al: Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 1994;83:2795.PubMedGoogle Scholar
  9. 9.
    Hopfenspirger MT, Parr SK, Townley RG, Agrawal DK: Attenuation of allergic airway inflammation and associated pulmonary functions by mycobacterial antigens is independent of IgE in a mouse model of asthma. Allergol Int 2002;51:21.CrossRefGoogle Scholar
  10. 10.
    Chong BT, Agrawal DK, Romero FA, Townley RG: Measurement of bronchoconstriction using whole-body plethysmograph: comparison of freely moving versus restrained guinea pigs. J Pharmacol Toxicol Methods 1998;39:163.PubMedCrossRefGoogle Scholar
  11. 11.
    Hamelmann E, Schwarze J, Takeda K, et al: Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am J Respir Crit Care Med 1997;156:766.PubMedGoogle Scholar
  12. 12.
    Dohi M, Tsukamoto S, Nagahori T, et al: Noninvasive system for evaluating the allergen-specific airway response in a murine model of asthma. Lab Invest 1999;79:1559.PubMedGoogle Scholar
  13. 13.
    Saloga J, Renz H, Lack G, et al: Development and transfer of immediate cutaneous hypersensitivity in mice exposed to aerosolized antigen. J Clin Invest 1993;91:133.PubMedCrossRefGoogle Scholar
  14. 14.
    Roche WR, Beasley R, Williams JH, Holgate ST: Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989;1:520.PubMedCrossRefGoogle Scholar
  15. 15.
    Blyth DI, Pedrick MS, Savage TJ, Hessel EM, Fattah D: Lung inflammation and epithelial changes in a murine model of atopic asthma. Am J Respir Cell Mol Biol 1996;14:425.PubMedGoogle Scholar
  16. 16.
    Brewster CE, Howarth PH, Djukanovic R, Wilson J, Holgate ST, Roche WR: Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 1990;3:507.Google Scholar
  17. 17.
    Chu HW, Halliday JL, Martin RJ, Leung DY, Szefler SJ, Wenzel SE: Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease. Am J Respir Crit Care Med 1998;158:1936.PubMedGoogle Scholar
  18. 18.
    Rankin JA, Picarella DE, Geba GP, et al: Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci USA 1996;93:7821.PubMedCrossRefGoogle Scholar
  19. 19.
    Lee JJ, McGarry MP, Farmer SC, et al: Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J Exp Med 1997;185:2143.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhu Z, Homer RJ, Wang Z, et al: Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999;103:779.PubMedGoogle Scholar
  21. 21.
    Brusselle GG, Kips JC, Tavernier JH, et al: Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin Exp Allergy 1994;24:73.PubMedCrossRefGoogle Scholar
  22. 22.
    Kips JC, Brusselle GG, Joos GF, et al: Importance of interleukin-4 and interleukin-12 in allergen-induced airway changes in mice. Int Arch Allergy Immunol 1995;107:115.PubMedCrossRefGoogle Scholar
  23. 23.
    Gharaee-Kermani M, Nozaki Y, Hatano K, Phan SH: Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis. Cytokine 2001;15:138.PubMedCrossRefGoogle Scholar
  24. 24.
    Huaux F, Liu T, McGarry B, Ullenbruch M, Phan SH: Dual roles of IL-4 in lung injury and fibrosis. J Immunol 2003;170:2083.PubMedGoogle Scholar
  25. 25.
    Sempowski GD, Derdak S, Phipps RP: Interleukin-4 and interferon-gamma discordantly reguiate collagen biosynthesis by functionally distinct lung fibroblast subsets. J Cell Physiol 1996;167:290.PubMedCrossRefGoogle Scholar
  26. 26.
    Trifilieff A, Fujitani Y, Coyle AJ, Kopf M, Bertrand C: IL-5 deficiency abolishes aspects of airway remodelling in a murine model of lung inflammation. Clin Exp Allergy 2001;31:934.PubMedCrossRefGoogle Scholar
  27. 27.
    Blyth DI, Wharton TF, Pedrick MS, Savage TJ, Sanjar S: Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody. Am J Respir Cell Mol Biol 2000;23:241.PubMedGoogle Scholar
  28. 28.
    Flood-Page P, Menzies-Gow A, Phipps S, et al: Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 2003;112:1029.PubMedCrossRefGoogle Scholar
  29. 29.
    Tanaka H, Komai M, Nagao K, Ishizaki M, et al: Role of interleukin-5 and eosinophils in allergen-induced airway remodeling in mice. Am J Respir Cell Mol Biol 2004;31:62.PubMedCrossRefGoogle Scholar
  30. 30.
    Groux H, Bigler M, de Vries JE, Roncarolo MG: Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996;184:19.PubMedCrossRefGoogle Scholar
  31. 31.
    Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH: Induction of tolerance by IL-10-treated dendritic cells. J Immunol 1997;159:4772.PubMedGoogle Scholar
  32. 32.
    Akbari O, De Kruyff RH, Umetsu DT: Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001;2:725.PubMedCrossRefGoogle Scholar
  33. 33.
    Kingsley CI, Karim M, Bushell AR, Wood KJ: CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol 2002;168:1080.PubMedGoogle Scholar
  34. 34.
    Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S: Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135.PubMedCrossRefGoogle Scholar
  35. 35.
    Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737.PubMedCrossRefGoogle Scholar
  36. 36.
    Shimura S, Andoh Y, Haraguchi M, Shirato K: Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma. Eur Respir J 1996;9:1395.PubMedCrossRefGoogle Scholar
  37. 37.
    Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima T: Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. Chest 1992;101:916.PubMedGoogle Scholar
  38. 38.
    Carroll N, Elliot J, Morton A, James A: The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405.PubMedGoogle Scholar
  39. 39.
    Fahy JV: Remodeling of the airway epithelium in asthma. Am J Respir Crit Care Med 2001;164:S46-S51.PubMedGoogle Scholar
  40. 40.
    Grunig G, Warnock M, Wakil AE, et al: Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998;282:2261.PubMedCrossRefGoogle Scholar
  41. 41.
    Wills-Karp M, Luyimbazi J, Xu X, et al: Interleukin-13: central mediator of allergic asthma. Science 1998;282:2258.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2007

Authors and Affiliations

  • Jehad H. Edwan
    • 1
    • 2
  • Devendra K. Agrawal
    • 1
    • 2
  1. 1.Department of Biomedical Sciences, Medical Microbiology & ImmunologyCreighton University School of MedicineOmaha
  2. 2.Department of Internal MedicineCreighton University School of MedicineOmaha
  3. 3.Medicine, and Medical Microbiology and ImmunologyCreighton University School of Medicine, CRISS IIOmaha

Personalised recommendations