Immune Responses in the Lung and Local Lymph Node of A/J Mice to Intranasal Sensitization and Challenge with Adjuvant-Free Ovalbumin

Abstract

Pathologic features of IgE-mediated allergic airway diseases include airway infiltration of inflammatory cells (eg, lymphocytes, plasma cells, and eosinophils) and mucous cell metaplasia (MCM) in airway epithelium. CD4+ T lymphocytes, specifically those producing a type 2 (Th2) cytokine profile, are necessary for the induction of IgE-mediated allergic airway responses. Most experimental models of IgE-mediated allergic airway disease use systemic (eg, intraperitoneal) administration of an allergen coupled with an adjuvant to sensitize animals. Cytokine changes are measured in a number of ways including in bronchoalveolar lavage fluid (BALF) or lymph node cells stimulated ex vivo. The primary objective of this study was to test the hypothesis that intranasal sensitization and challenge of mice with ovalbumin in the absence of an adjuvant will induce the pathologic features that are characteristic of IgE-mediated allergic airway disease. Another objective was to determine if intranasal delivery of this allergen will result in the induction of a profile of cytokine gene expression in the lung and tracheobronchial (TB) lymph node, that is typical of immunologic changes associated with IgE-mediated allergic airway disease. Only mice that were intranasally sensitized and challenged with ovalbumin exhibited pulmonary lesions that included marked MCM in the respiratory epithelium lining the nasal and pulmonary airways, and an associated mixed inflammatory cell influx consisting of lymphocytes, plasma cells and eosinophils. Ovalbumin-treated mice also exhibited enhanced expression of the Th2 cytokine mRNAs IL-4, IL-5, IL-10, and IL-13 in the lung and IL-4 in the TB lymph node, and concurrent increases in ovalbumin-specific IgE in the serum. The results of this study indicate that A/J mice intranasally instilled with ovalbumin without adjuvant have the hallmark histopathologic and immunologic features of IgE-mediated allergic airway disease of humans.

Keywords

Intranasal sensitization and challenge nasal and pulmonary airways A/J mice Th2 cytokines ovalbumin adjuvant-free morphologic features of allergic airway disease tracheobronchial lymph node.

References

Beach JR (2000). Immunologic versus toxicologic mechanisms in airway responses. In: Occupational Medicine: State of the Art Reviews, Volume 15, No. 2, Hanley and Belfus, Inc, Philadelphia, pp 455— 469.

Bellinghausen I. , Knop J. , Saloga J. (2001). The role of Interleukin 10 in the regulation of allergic immune responses . Int Arch Allergy Immunol 126: 97—101.

Blaikie L. , Basketter DA (1999). Experience with a mouse intranasal test for the predictive identification of respiratory sensitization potential of proteins . Food Chem Toxicol 37: 889—896.

Busse WW , Holgate ST (2000). Allergic and non-allergic rhinitis. In: Asthma and Rhinitis, Volume 1, Second Edition. Blackwell Science Ltd, Osney Meade, Oxford, pp 232—244.

Condie R. , Herring A. , Koh WS , Lee M. , Kaminski NE (1996). Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2. JBiol Chem 271(22): 13175—13183.

Denzeler KL , Farmer SC , Crosby JR , Borchers M. , Cieslewicz G. , Larson KA , Cormier-Regard S. , Lee NA , Lee JJ (2000). Eosinophil major basic protein-1 does not contribute to allergen-induced airway pathologies in mouse models of asthma. J Immunol 165: 5509—5517.

Foster PS , Ming Y. , Matthei KI , Young IG , Temelkovski J. , Kumar RK (2000). Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma. Lab Invest 80: 655—662.

Frew AJ (1996). The immunology of respiratory allergies. Toxicol Lett 86: 65—72.

Gilliland G. , Perrin S. , Blanchard K. , Bunn HF (1990). Analysis of cytokine mRNA and DNA: detection and quantitation by competitive polymerase chain reaction . Proc Natl Acad Sci USA 87(7): 2725—2729.

10.

Hamelman E. , Oshiba A. , Loader J. , Larsen GL , Gleich G. , Lee J. , Gelfand EW (1997). Antiinterleukin-5 antibody prevents airway hyperresponsiveness in a Murine model of airway sensitization . Am J Respir Crit Care Med 155: 819—825.

11.

Harkema JR , Plopper CG , Hyde DM , St. George JA , Dungworth DL (1987). Effects of an ambient level of ozone on primate nasal epithelial mucosubstances. Quantitative histochemistry. Am J Pathol 127: 90—96.

12.

Holgate, ST (2000). Inflammatory and structural changes in the airways of patients with asthma. Resp Med 94: Supplement D, S3—S6.

13.

Karras JG , McGraw K. , McKay, Cooper , SR , Lerner D. , Lu T. , Walker C. , Dean NM , Monia BP (2000). Inhibition of antigen-induced eosinophilia and late phase hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma. J Immunol 164: 5409—5415.

14.

Kay AB (2001). Allergy and allergic diseases. N Engl J Med 344(1): 30—37.

15.

Kimber I. , and Dearman R. (1997). Predicitve assessment of respiratory sensitizing potential of chemicals in mice. In: Toxicology of Chemical Respiratory Hypersensitivity. Taylor and Francis Limited , Bristol, Pennsylvania, pp 121—134.

16.

Lee CG , Homer RJ , Cohn L. , Link H. , Jung S. , Craft JE , Graham BS , Johnson TR , Elias JA (2002). Transgenic overexpression of interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and- independent pathways. J. Biol Chem 277(38): 35466—35474.

17.

Makela MJ , Kanehiro A. , Borish L. , Dakhama A. , Loader J. , Joetham A. , Xing Z. , Jordana M. , Larsen GL , Gelfand EW (2000). IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization . Proc Natl Acad Sci USA 97(11): 6007—6012.

18.

Okano M. , Nishizaki K. , Abe M. , Wang M-M. , Yoshino T. , Satoskar AR , Masuda Y. , HarnJr DA (1999). Strain-dependent induction of allergic rhinitis without adjuvant in mice. Allergy 54: 593—660.

19.

Rajananthanan P. , Attard GS , Sheikh NA , Morrow WJW (1999). Evaluation of novel aggregate structures as adjuvants: Composition, toxicity studies and humoral responses. Vaccine 17: 715—730.

20.

Robinson MK , Babcock LS , Horn PA , Kawabata TT (1996). Specific antibody responses to subtilisin carslberg (Alcalase) in Mice: Development of an intranasal exposure model. Fundam Appl Toxicol 34: 15—24.

21.

Shen H. , Liu J. , Liu F. , Wang X. , Lin X. , Xu Z. , Huang G. , Yuan S. ( 2002). The observation of local immune response in the lungs from antigen-sensitized and challenged mice (article in Chinese). Zhonghua Jie He HE Hu Xi Za Zhi 25(3): 156—158

22.

Stampfli MR , Wiley RE , Neigh GS , Gajewska BU , Lei X-F. , Snider DP , Xing Z. , Jordana M. (1998). GM-CSF Transgene expression in the airways allows aerosolized ovalbumin to induce allergic sensitization in mice. J Clin Invest 102(9): 1704—1714.

23.

Steiger D. , Hotchkiss J. , Baja L. , Harkema J. , Basbaum C. (1995). Concurrent increases in the storage and release of mucin-like molecules by rat airway epithelial cells in response to bacterial endotoxin. Am J Respir Cell Mol Biol 12: 307—314.

24.

van de Rijn M. , Mehlhop PD , Judkins A. , Rothenberg ME , Luster AD , Oettgen HC (1998). A Murine model of allergic rhinitis: Studies on the role of IgE in pathogenesis and analysis of the eosinophil influx elicited by allergen and eotaxin. J Allergy Clin Immunol 102: 65—74.

25.

Vanden Heuvel JP , Clark GC , Thompson CL , McCoy Z. , Miller CR , Lucie GW , Bell DA (1993). CYP1A1 mRNA levels as a human exposure biomarker: Use of quantitative polymerase chain reaction to measure CYP1A1 expression in human peripheral blood lymphocytes . Carcinogenesis 14(10): 2003—2006.

26.

Wills-Karp M. (1999). Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol 17: 255—281.

27.

Wills-Karp M. , Luyimbazi J. , Xu X. , Schofield B. , Neben TY , Karp CL , Donaldson DD (1998). Interleukin-13: Central mediator of allergic asthma. Science 282: 2258—2261.

28.

Woolhiser MR , Munson AE , Meade BJ (2000). Immunological responses of mice following administration of natural rubber latex proteins by different routes of exposure. Toxicol Sci 55: 343—351.

29.

Yang X. , Wang S. , Fan Y. , Han X. (2000). IL-10 deficiency prevents IL-5 overproduction and eosinophilic inflammation in a Murine model of asthma-like reaction. Eur J Immunol 30(2): 382— 391.

30.

Young JT (1981). Histopathologic examination of the rat nasal cavity . Fundam Appl Toxicol 1: 309—312.

31.

Yssel H. , Groux H. (2000). Characterization of T cell subpopulations Involved in the pathogenesis of asthma and allergic diseases. Int Arch Allergy Immunol 121: 10—18.