A mouse model of allergic rhinitis mimicking human pathology

Abstract

Introduction. Allergic rhinitis (AR) is an IgE-mediated inflammation of the upper respiratory tract. More than 400 million people worldwide suffer from this pathology. According to the current concept AR develops through a Th2-dependent mechanism involving cytokines (IL-4, IL-5 and IL-13) and pro-inflammatory cells, primarily eosinophils. Improvement of current therapy, the development of new ways of AR treatment and understanding of pathogenesis of the disease are urgent tasks of biomedicine, which are needed of appropriate animal models.

The aim of the study was to develop a mouse model of allergic rhinitis, which mimics the main features of human pathology.

Material and methods. Sensibilization with the allergen ovalbumin (OVA) was performed by three subcutaneous immunizations at a dose of 20 µg. After the sensitization mice Balb/c were received 25 µl of solution of the same allergen (in concentration 10 mg/ml) intranasally. Nasal hyperreactivity was assessed as frequency of sneezing and nasal rubbing. The levels of serum immunoglobulins and cytokines in the supernatants of lymph node cells were measured by ELISA. The mRNA expression of cytokine genes in the nasal mucosa was determined by quantitative PCR. Histological analysis was used to assess the level of inflammation in the upper respiratory tract.

Results. Subcutaneous immunizations followed by intranasal challenge of mice with an allergen according to the described protocol induced main features of AR, such as increased nasal hyperreactivity (an increase in the number of sneezes by 11 times and scratching of the nose by 8 times, compared to mice of control group), an increased level of allergen specific IgE antibodies. The inflammation of the upper respiratory tract was also observed that expressed in: 5-fold increase in the number cells infiltrating nasal mucosa, 3-fold increase in the area of cell infiltrates, 1.4 times increase in the proportion of mucous secreting goblet cells in the respiratory epithelium. An increased production of Th2-cytokines (IL-4, IL-5 and IL-13) by submandibular lymph node cells and the expression of mRNA of the corresponding genes (Il4, Il5 and Il13) in the nasal mucosa revealed that the mice developed AR phenotype through Th2-dependent mechanisms.

The common AR pharmacotherapy includes antihistamines, antileukotriene and corticosteroids. To test the developed mouse model of AR we conducted an experimental therapy using these drugs. As a result, a significant decrease in main AR manifestations such as nasal hyperreactivity, inflammation of the nasal mucosa and remodeling of the respiratory tract were revealed.

Conclusion. A mouse model of AR mimicking main pathological features was developed: nasal hyperreactivity, increased levels of allergen specific IgE antibodies, infiltration of the nasal mucosa with pro-inflammatory cells. AR phenotype induced in mice developed through Th2-dependent mechanism. Antihistamines, antileukotrienes and corticosteroids were tested on the developed mouse model of AR. These drugs demonstrated effects similar to those in clinical practice, which confirms that the developed mouse model of AR is adequate to clinical observations. The developed model can be used to study the pathogenesis of AR, as well as to test the effectiveness of new drugs.

Keywords:allergy; allergic rhinitis; laboratory animal models; modeling of diseases; ovalbumin

For citation: Shilovskiy I.P., Barvinskaia E.D., Kaganova M.M., Kovchina V.I., Yumashev K.V., Korneev A.V., Nikolskii A.A., Vishnyakova L.I., Brylina V.E., Rusak T.E., Kurbachova O.M., Dyneva M.E., Petukhova O.A., Gudima G.O., Kudlay D.A., Khaitov M.R. Reproduction of clinical and pathophysiological signs of allergic rhinitis on mouse model mimicking human pathology. Immunologiya. 2022; 43 (6): 654–72. DOI: https://doi.org/10.33029/0206-4952-2022-43-6-654-672 (in Russian)

Funding. The study was supported by the grant of Russian Science Foundation No. 19-15-00272. URL: https://rscf.ru/project/19-15-00272/

Conflict of interests. The authors declare no conflict of interests.

Authors’ contribution. Study conception and design – Shilovskiy I.P., Khaitov M.R.; material collection and processing – Barvinskaia E.D., Nikolskii A.A., Kovchina V.I., Vishnyakova L.I., Yumashev K.V., Korneev A.V., Kaganova M.M., Rusak T.E.; statistical processing – Barvinskaia E.D., Kaganova M.M.; manuscript preparation – Shilovskiy I.P., Barvinskaia E.D., Kaganova M.M.; editing – Gudima G.O., Kudlay D.A., Kurbacheva O.M., Dyneva M.E., Petukhova O.A., Kaganova M.M., Brylina V.E.

References

1. Astafieva N.G., Baranov A.A., Vishneva E.A., Daiсhes N.A., Zhestkov A.V., Ilyina N.I., Karneeva O.V., Karpova E.P., Kim I.A., Kryukov A.I., Kurbacheva O.M., Meshkova R.Y., Namazova-Baranova L.S., Nenasheva N.M., Novik G.A., Nosulya E.M., Pavlova K.S., Pampura A.N., Svistushkin V.M., Selimzyanova L.R., Khaitov M.R., Khaitov R.M. Allergic rhinitis. Clinical guidelines. Moscow: RAAСI, 2020. 70 p. (in Russian)

2. Atipas K., Kanjanawasee D., Tantilipikorn P. Intradermal allergen immunotherapy for allergic rhinitis: current evidence. J. Pers. Med. 2022; 12 (8): 1–13. DOI: https://www.doi.org/10.3390/jpm12081341

3. Bousquet J., Schünemann H.J., Togias A., Bachert C., et al. Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence. J. Allergy Clin. Immunol. 2020; 145 (1): 70–80. DOI: https://www.doi.org/10.1016/j.jaci.2022.04.016

4. Meng Y., Wang C., Zhang L. Advances and novel developments in allergic rhinitis. Allergy. 2020; 75 (12): 3069–76. DOI: https://www.doi.org/10.1111/all.14586

5. Kozlov V.A., Tikhonova E.P., Savchenko A.A., Kudryavtsev I.V., Andronova N.V., Anisimova E.N., Golovkin A.S., Demina D.V., Zdzitovetsky D.E., Kalinina Y.S., Kasparov E.V., Kozlov I.G., Korsunsky I.A., Kudlay D.A., Kuzmina T.Yu., Minoranskaya N.S., Prodeus A.P., Starikova E.A., Cherdantsev D.V., Chesnokov A.B., P.A. Gear, A.G. Borisov. Clinical immunology. A practical guide for infectious diseases. Krasnoyarsk: Polikor, 2021. 563 p. (in Russian)

6. Babakhin A.A. Shilovskiy I.P., Andreev I.V., Kozmin L.D., et al. Experimental allergen-specific immunotherapy with the use of a Timpol allergovaccine as exemplified by the murine model of IgE-dependent bronchial asthma. Immunologiya. 2012; 33 (3): 134–41. (in Russian)

7. Dorofeeva Y., Shilovskiy I., Tulaeva I., Focke-Tejkl M., et al. Past, present, and future of allergen immunotherapy vaccines. Allergy. 2021; 76 (1): 131–49. DOI: https://www.doi.org/10.1111/all.14300

8. Papadopoulos N.G., Aggelides X., Stamataki S., Prokopakis E., et al. New concepts in pediatric rhinitis. Pediatr Allergy Immunol. 2021; 32 (4): 635–46. DOI: https://www.doi.org/10.1111/pai.13454

9. Bernstein D.I., Schwartz G., Bernstein J.A. Allergic Rhinitis: Mechanisms and Treatment. Immunol. Allergy Clin. North Am. 2016; 36 (2): 261–78. DOI: https://www.doi.org/10.1016/j.iac.2015.12.004

10. Gudima G.O., Khaitov M.R., Kudlay D.A. Mechanisms of allergic reactions (educational and methodical manual). Moscow: GEOTAR-Media, 2022. 80 p. (in Russian)

11. Gusniev S.A., Polner S.A., Mikhaleva L.M., Ilyina N.I., et al. Influence of interleukin-33 gene expression on clinical and morphological characteristics of the nasal mucosa in allergic rhinitis. Immunologiya. 2021; 42 (1): 68–79. DOI: https://www.doi.org/10.33029/0206-4952-2021-42-1-68-79 (in Russian)

12. Shilovskiy I.P., Dyneva M.E., Kurbacheva O.M., Kudlay D.A., et al. The role of interleukin-37 in the pathogenesis of allergic diseases. Acta Naturae. 2019; 11 (4): 54–64. DOI: https://www.doi.org/10.32607/20758251-2019-11-4-54-64

13. Yang C., Chen N., Tang X.L., Qian X.H., et al. Immunomodulatory effects of IL-33 and IL-25 in an ovalbumin-induced allergic rhinitis mouse model. J. Biol. Regul. Homeost. Agents. 2021; 35 (2): 571–81. DOI: https://www.doi.org/10.23812/20-615-A

14. Shilovskiy I., Nikonova A., Barvinskaia E., Kaganova M., Nikolsky A.A., Vishnyakova L., Kovchina V., Yumashev K.., Korneev A., Petukhova O., Kudlai D., Smirnov V., Andreev S., Kozhikhova K., Shatilov A., Shatilova A., Maerle A., Sergeev I., Trofimov D., Khaitov M. Anti-inflammatory effect of siRNAs targeted il-4 and il-13 in a mouse model of allergic rhinitis. Allergy. 2022; 77 (9): 2829–32. DOI: https://www.doi.org/10.1111/all.15366

15. Luan Z.L., Wang Y.N., Wang H.T. Research progress of animal model of allergic rhinitis. Lin Chung. Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2016; 30 (13): 1090–94. DOI: https://www.doi.org/10.13201/j.issn.1001-1781.2016.13.022

16. Choi S., Jung M.A., Hwang Y.H., Pyun B.J., et al. Anti-allergic effects of Asarum heterotropoides on an ovalbumin-induced allergic rhinitis murine model. Biomed. Pharmacother. 2021; 141: 1–10. DOI: https://www.doi.org/10.1016/j.biopha.2021.111944

17. Bae J.S., Kim S.H., Kim J.H., Kim E.H., et al. Effects of low-level laser irradiation in a mouse model of allergic rhinitis. Lasers Surg. Med. 2020; 52 (4): 347–57. DOI: https://www.doi.org/10.1002/lsm.2314

18. Wang Y., Cao Z., Zhao H., Ren Y., et al. Bisphenol a exacerbates allergic inflammation in an ovalbumin-induced mouse model of allergic rhinitis. J. Immunol. Res. 2020; 1–9. DOI: https://www.doi.org/10.1155/2020/7573103

19. Kar M., Muluk N.B., Bafaqeeh S.A., Cingi С. Consensus on the methodology for experimental studies in allergic rhinitis. Int. J. Pediatr. Otorhinolaryngol. 2019; 121: 68–71. DOI: https://www.doi.org/10.1016/j.ijporl.2019.03.009

20. Conrad M.L., Yildirim A.O., Sonar S.S., Kiliç A., et al. Comparison of adjuvant and adjuvant-free murine experimental asthma models. Clin. Exp. Allergy. 2009; 39 (8): 1246–54. DOI: https://www.doi.org/10.1111/j.1365-2222.2009.03260.x

21. Valenta R., Kraft D. Recombinant allergens for diagnosis and the­rapy of allergic diseases. Curr. Opin. Immunol. 1995; 7 (6): 751–56. DOI: https://www.doi.org/10.1016/0952-7915(95)80043-3

22. Zhang Y.L., Shin H.J., Lee J.H., Lee J., et al. Antiallergic effect of hizikia fusiformis in an ovalbumin-induced allergic rhinitis mouse model. Clin. Exp. Otorhinolaryngol. 2019; 12 (2): 196–205. DOI: https://www.doi.org/10.21053/ceo.2019.00094

23. Dai L. Zhong L.L.D., Kun W., Lam W.C., et al. An external CAM therapy (Tian Jiu) versus placebo in treatment of allergic rhinitis: a pilot single-blinded, three-arm, randomized controlled study. Evidence-based Complement. Altern. Med. 2019; 2–4. DOI: https://www.doi.org/10.1155/2019/6369754

24. Joo S.H., Hyun K.J., Kim Y.H. Korean modification of the nasal provocation test with house dust mite antigen following the EAACI Guidelines. Clin. Exp. Otorhinolaryngol. 2021; 14 (4): 382–9. DOI: https://www.doi.org/10.21053/ceo.2020.00563

25. Ji K.Y., Jung D.H., Pyun B.J., Kim Y.J., et al. Angelica gigas extract ameliorates allergic rhinitis in an ovalbumin-induced mouse model by inhibiting Th2 cell activation. Phytomedicine. 2021; 93: 1–9. DOI: https://www.doi.org/10.1016/j.phymed.2021.153789

26. Cho J.Y., Miller M., Baek K.J., Han J.W., et al. Inhibition of airway remodeling in IL-5-deficient mice. J. Clin. Invest. 2004; 113 (4): 551–60. DOI: https://www.doi.org/10.1172/JCI19133

27. Pirogov A.B., Prikhodko A.G., Perelman J.M. Interrelationship of IFN-γ, IL-4, pituitary-thyroid and pituitary-adrenocortical systems in cold airway hyperresponsiveness in patients with asthma. Immunologiya. 2021; 42 (5): 480–9. DOI: https://www.doi.org/10.33029/0206-4952-2021-42-5-480-489 (in Russian)

28. Shilovskiy I.P., Sundukova M.S., Babakhin А.А., Gaisina A.R., et al. Experimental protocol for development of adjuvant-free murine chronic model of allergic asthma. J. Immunol. Methods. 2019; 468: 10–9. DOI: https://www.doi.org/10.1016/j.jim.2019.03.002

29. Nakanishi W., Yamaguchi S., Matsuda A., Suzukawa M., et al. IL-33, but not IL-25, is crucial for the development of house dust mite antigen-induced allergic rhinitis. PLoS One. 2013; 8 (10): 9–11. DOI: https://www.doi.org/10.1371/journal.pone.0078099

30. Wang C., Liu Q., Chen F., Xu W., et al. IL-25 Promotes Th2 immunity responses in asthmatic mice via nuocytes activation. PLoS One. 2016; 11 (9): 1–13. DOI: https://www.doi.org/10.1371/journal.pone.0162393

31. Deng C., Peng N., Tang Y., Yu N., et al. Roles of IL-25 in type 2 inflammation and autoimmune pathogenesis. Frontiers in Immunology. 2021; 12: 2051. DOI: https://www.doi.org/10.3389/fimmu.2021.691559

32. Cheng D., Xue Z., Yi L., Shi H., et al. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am. J. Respir. Crit. Care Med. 2014; 190 (6): 639–48. DOI: https://www.doi.org/10.1164/rccm.201403-0505OC

33. Wu Y.H., Lai A.C.Y., Chi P.Y., Thio C.L.P., et al. Pulmonary IL-33 orchestrates innate immune cells to mediate respiratory syncytial virus-evoked airway hyperreactivity and eosinophilia. Allergy. 2020; 75 (4): 818–30. DOI: https://www.doi.org/10.1111/all.14091

34. Chan B.C.L. Lam C.W.K., Tam L.S., Wong C.K. IL33: Roles in allergic inflammation and therapeutic perspectives. Frontiers in Immunology. Front Immunol. 2019; 10: 1–11. DOI: https://www.doi.org/10.3389/fimmu.2019.00364

35. Yao X.J., Liu X.F., Wang X.D. Potential role of interleukin-25/interleukin-33/thymic stromal lymphopoietin-fibrocyte axis in the pathogenesis of allergic airway diseases. Chin. Med. J. 2018; 131 (16): 1983–89. DOI: https://www.doi.org/10.4103/0366-6999.238150

36. Tyurin Y.A., Lissovskaya S.A., Fassahov R.S., Mustafin I.G., et al. Cytokine profile of patients with allergic rhinitis caused by pollen, mite, and microbial allergen sensitization. J. Immunol. Res. 2017; 2017: 1–7. DOI: https://www.doi.org/10.1155/2017/3054217

37. Shilovskiy I., Sundukova M.S., Korneev A.V., Nikolskii A.A., et al. The mixture of siRNAs targeted to IL-4 and IL-13 genes effectively reduces the airway hyperreactivity and allergic inflammation in a mouse model of asthma. Int. Immunopharmacol. 2022; 103. DOI: https://www.doi.org/10.1016/j.intimp.2021.108432

38. Klimek L., Sperl A., Becker S., Mösges R., et al. Current therapeutical strategies for allergic rhinitis. Expert Opin. Pharmacother. 2019; 20 (1): 83–9. DOI: https://www.doi.org/10.1080/14656566.2018.1543401

39. Thangam E.B., Jemima E.A., Singh H., Baig M.S., et al. The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: The hunt for new therapeutic targets. Front. Immunol. 2018; 9: 1–9. DOI: https://www.doi.org/10.3389/fimmu.2018.01873

40. Shirasaki H., Himi T. Role of cysteinyl leukotrienes in allergic rhinitis. Adv. Otorhinolaryngol. 2016; 77: 40–5. DOI: https://www.doi.org/10.1159/000441871

41. Castro-Rodriguez J.A., Rodriguez-Martinez C.E., Ducharme F.M. Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review. Pediatr. Pulmonol. 2018; 53 (12): 1670–77. DOI: https://www.doi.org/10.1002/ppul.24176

42. Barnes P.J. Corticosteroid effects on cell signaling. Eur. Respir. J. 2006; 27 (2): 413–26. DOI: https://www.doi.org/0.1183/09031936.06.00125404

43. Miyajima I., Dombrowicz D., Martin T.R., Ravetch J.V., et al. Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc gammaRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis. J. Clin. Invest. 1997; 99 (5). 901–14. DOI: https://www.doi.org/10.1172/JCI119255

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)


JOURNALS of «GEOTAR-Media»