Allergen immunotherapy: on the path to achieving immune tolerance

• Ksenia S. Pavlova
• Daria O. Timoshenko
• Igor S. Gushchin
• Oksana M. Kurbacheva

Abstract

Allergen immunotherapy (AIT) is one of the main methods for the pathogenetic treatment of IgE-mediated allergic diseases. The AIT degrades the sensitivity to a significant allergen and the clinical symptoms severity, reduces the risk of medications use, prevents the asthma and new sensitization. AIT-induced tolerance is an active highly-regulated state of immunity resistance to the allergen and is mediated by a complex interaction between various cells of the innate and adaptive immune system. Numerous cellular and molecular studies have brought us closer to understanding the processes that characterize allergic inflammation and AIT-induced immune tolerance. However, the AIT mechanism remains unclear. An understanding of the immune response modification during AIT is necessary for the physicians to predict the therapeutic effects and the timing of their achievement, assess the possibility of combining AIT with other methods of therapy, and minimize the risks of adverse events. This review describes modern conception of the IgE-mediated allergic reactions mechanisms and the AIT points of action.

Keywords:allergen-specific immunotherapy; allergen immunotherapy; AIT; mechanisms of allergen immunotherapy; immune tolerance

References

1. Des Roches A., Paradis L., Menardo J.L., Bouges S., et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol. 1997; 99 (4): 450–3. DOI: https://doi.org/10.1016/s0091-6749(97)70069-1

2. Dhami S., Nurmatov U., Arasi S., Khan T. et al. Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta-analysis. Allergy. 2017; 72 (11): 1597–631. DOI: https://doi.org/10.1111/all.13201

3. Feng B., Wu J., Chen B., Xiang H. et al. Efficacy and safety of sublingual immunotherapy for allergic rhinitis in pediatric patients: A meta-analysis of randomized controlled trials. Am J Rhinol Allergy. 2017; 31 (1): 27–35. DOI: https://doi.org/10.2500/ajra.2017.31.4382

4. Kim J.M., Lin S.Y., Suarez-Cuervo C., Chelladurai Y. et al. Allergen-specific immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review. Pediatrics. 2013; 131 (6): 1155–67. DOI: https://doi.org/10.1542/peds.2013-0343

5. Li Y., Yu S.Y., Tang R., Zhao Z.T. et al. Sublingual immunotherapy tablets relieve symptoms in adults with allergic rhinitis: a meta-analysis of randomized clinical trials. Chin Med J (Engl). 2018; 131 (21): 2583–8. DOI: https://doi.org/10.4103/0366-6999.244108

6. Mösges R., Santiago V.A., Allekotte S., Jahed N. et al. Subcutaneous immunotherapy with depigmented-polymerized allergen extracts: a systematic review and meta-analysis. Clin Transl Allergy. 2019; 9 (29). DOI: https://doi.org/10.1186/s13601-019-0268-5  

7. Purello-D’Ambrosio F., Gangemi S., Merendino R.A., Isola S. et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy. 2001; 31 (8): 1295–302. DOI: https://doi.org/10.1046/j.1365-2222.2001.01027.x

8. Radulovic S., Calderon M.A., Wilson D., Durham S. Sublingual immunotherapy for allergic rhinitis. Cochrane Database of Systematic Reviews 2010; 12: CD002893. DOI: https://doi.org/10.1002/14651858.CD002893.pub2

9. Tahamiler R., Saritzali G., Canakcioglu S. Long-term efficacy of sublingual immunotherapy in patients with perennial rhinitis. Laryngoscope. 2007; 117 (6): 965–9. DOI: https://doi.org/10.1097/MLG.0b013e31804f8141

10. Wilson D.R., Lima M.T., Durham S.R. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy. 2005; 60 (1): 4–12. DOI: https://doi.org/10.1111/j.1398-9995.2005.00699.x

11. Yarilin A.A. Immunology. Мoscow: GEOTAR-Media, 2010. 752 p. (in Russian)

12. O’Shea J.J., Paul W.E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010; 327 (5969): 1098–102. DOI: https://doi.org/10.1126/science.1178334

13. Zheng Y., Chaudhry A., Kas A., deRoos P. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature. 2009; 458 (7236): 351–6. DOI: https://doi.org/10.1038/nature07674

14. Chaudhry A., Rudra D., Treuting P., Samstein R.M. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009; 326 (5955): 986–91. DOI: https://doi.org/10.1126/science.1172702

15. Kim B.S., Kim I.K., Park Y.J., Kim Y.S. et al. Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma. Proc Natl Acad Sci U S A. 2010; 107 (19): 8742–7. DOI: https://doi.org/10.1073/pnas.0911756107

16. Miyara M., Yoshioka Y., Kitoh A., Shima T. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009; 30 (6): 899–911. DOI: https://doi.org/10.1016/j.immuni.2009.03.019

17. Hoffmann P., Eder R., Boeld T.J., Doser K. et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. 2006; 108 (13): 4260–7. DOI: https://doi.org/10.1182/blood-2006-06-027409

18. Iyer S.S., Cheng G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol. 2012; 32 (1): 23–63. DOI: https://doi.org/10.1615/critrevimmunol.v32.i1.30

19. Wisniewski J., Agrawal R., Woodfolk J.A. Mechanisms of tolerance induction in allergic disease: integrating current and emerging concepts. Clin Exp Allergy. 2013; 43 (2): 164–76. DOI: https://doi.org/10.1111/cea.12016

20. van de Veen W., Wirz O.F., Globinska A., Akdis M. Novel mechanisms in immune tolerance to allergens during natural allergen exposure and allergen-specific immunotherapy Curr Opin Immunol. 2017; 48: 74–81. DOI: https://doi.org/10.1016/j.coi.2017.08.012

21. Gushchin I.S. Doubts and hopes of allergology. Immunologiya. 2023; 44 (4): 471–80. DOI: https://doi.org/10.33029/0206-4952-2023-44-4-471-480 (in Russian)

22. Camelo A., Rosignoli G., Ohne Y., Srewart R.A. et al. IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells. Blood advances. 2017; 1 (10): 577–89. DOI: https://doi.org/10.1182/bloodadvances.2016002352

23. Zhou W., Toki S., Zhang J., Goleniewksa K. et al. Prostaglandin I2 signaling and inhibition of group 2 innate lymphoid cell responses. Am J Respir Crit Care Med. 2016; 193 (1): 31–42. DOI: https://doi.org/10.1164/rccm.201410-1793OC

24. Li B.W., Hendriks R.W: Group 2 innate lymphoid cells in lung inflammation. Immunology. 2013; 140 (3): 281–7. DOI: https://doi.org/10.1111/imm.12153

25. Rank M.A., Kobayashi T., Kozaki H., Bartemes K.R. et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009; 123 (5): 1047–54. DOI: https://doi.org/10.1016/j.jaci.2009.02.026

26. Wang Y.H., Angkasekwinai P., Lu N., Voo K.S. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med. 2007; 204 (8): 1837–47. DOI: https://doi.org/10.1084/jem.20070406

27. Tong P., Wesemann D.R. Molecular Mechanisms of IgE Class Switch Recombination. Curr Top Microbiol Immunol. 2015; 388: 21–37. DOI: https://doi.org/10.1007/978-3-319-13725-4_2

28. Locksley R.M. Asthma and allergic inflammation. Cell. 2010; 140 (6): 777–83. DOI: https://doi.org/10.1016/j.cell.2010.03.004

29. Hams E., Bermingham E.R., Fallon P.G. Macrophage and innate lymphoid cell interplay in the genesis of fibrosis. Front Immunol. 2015; 6: 597. DOI: https://doi.org/10.3389/fimmu.2015.00597

30. Mukai K., Tsai M., Saito H., Galli S.J. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev. 2018; 282 (1): 121–50. DOI: https://doi.org/10.1111/imr.12634

31. Yao Y., Chen C.L., Yu D., Liu Z. Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy. Allergy. 2021; 76 (2): 456–70. DOI: https://doi.org/10.1111/all.14639

32. Smirnov D.S., Donetskova A.D., Litvina M.M., Nikonova M.F., Mitin A.N., Kurbacheva O.M. Analysis of FOXP3 isoforms expression by regulatory T cells from peripheral blood in allergic rhinitis before and afterspecific immunotherapy. Immunologiya. 2018; 39 (5-6): 282–6. DOI: http://dx.doi.org/10.18821/0206-4952-2018-39-5-6-282-286 (in Russian)

33. Nikonova M.F., Donetskova A.M., Andreev I.V., Sankov M.N., Martynov A.I., Latischev S. L., Yarilin A.A. The biological action of allergen preparations from the plant pollen in the culture of human lymphocytes. Immunologiya. 2012; 33 (2): 86–9. (in Russian)

34. Shamji M.H.; Larson D.; Eifan A.; Scadding G.W. et al. Differential induction of allergen-specific IgA responses following timothy grass subcutaneous and sublingual immunotherapy. J Allergy Clin Immunol. 2021; 148 (4): 1061–71.e11. DOI: https://doi.org/10.1016/j.jaci.2021.03.030

35. Platts-Mills T.A., von Maur R.K., Ishizaka K., Norman P.S. et al. IgA and IgG anti-ragweed antibodies in nasal secretions. Quantitative measurements of antibodies and correlation with inhibition of histamine release. J Clin Invest. 1976; 57 (4): 1041–50. DOI: https://doi.org/10.1172/JCI108346

36. Reisinger J., Horak F., Pauli G., van Hage M. et al. Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity. J Allergy Clin Immunol. 2005; 116 (2): 347–54. DOI: https://doi.org/10.1016/j.jaci.2005.04.003

37. La Rosa M., Ranno C., Andre C., Carat F. et al. Double-blind placebo-controlled evaluation of sublingual-swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 1999; 104 (2 Pt 1): 425–32. DOI: https://doi.org/10.1016/s0091-6749(99)70388-x

38. Troise C., Voltolini S., Canessa A., Pecora S. et al. Sublingual immunotherapy in Parietaria pollen-induced rhinitis: A double-blind study. J Investig Allergol Clin Immunol. 1995; 5 (1): 25–30. PMID: 7551201

39. Bahceciler N.N., Arikan C., Taylor A., Akdis M. et al. Impact of sublingual immunotherapy on specific antibody levels in asthmatic children allergic to house dust mites. Int Arch Allergy Immunol. 2005; 136 (3): 287–94. DOI: https://doi.org/10.1159/000083956

40. James L.K., Shamji M.H., Walker S.M., Wilson D.R. et al. Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. J Allergy Clin Immunol. 2011; 127 (2): 509–16.e5. DOI: https://doi.org/10.1016/j.jaci.2010.12.1080

41. Novak N., Mete N., Bussmann C., Maintz L. et al. Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2. J Allergy Clin Immunol. 2012; 130 (5): 1153–8. DOI: https://doi.org/10.1016/j.jaci.2012.04.039

42. Ferstl R., Frei R., Schiavi E., Konieczna P. et al. Histamine receptor 2 is a key influence in immune responses to intestinal histamine-secreting microbes. J Allergy Clin Immunol. 2014; 134 (3): 744–6.e3. DOI: https://doi.org/10.1016/j.jaci.2014.04.034

43. Sahiner U.M., Giovannini M., Escribese M.M., Paoletti G. et al. Mechanisms of Allergen Immunotherapy and Potential Biomarkers for Clinical Evaluation. J Pers Med. 2023; 13 (5): 845. DOI: https://doi.org/10.3390/jpm13050845

44. Shamji M.H., Kappen J.H., Akdis M., Jensen-Jarolim E. et al. Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper. Allergy. 2017; 72 (8): 1156–73. DOI: https://doi.org/10.1111/all.13138

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