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Licensed Unlicensed Requires Authentication Published by De Gruyter April 27, 2017

Desensitization to chemical and food sensitivities by low-dose immunotherapy ascertained by provocation neutralization is associated with reduced influx of calcium ions into lymphocytes

Basant K. Puri, John McLaren Howard and Jean A. Monro

Abstract

Background

Food and chemical sensitivities have detrimental effects on health and the quality of life. The natural course of such sensitivities can potentially be altered through various types of allergen-specific immunotherapy, including low-dose immunotherapy. The molecular mechanism by which low-dose immunotherapy causes desensitization has not thus far been elucidated. While resting lymphocytes maintain a low cytosolic calcium ion concentration, antigen receptor signaling results in calcium ion influx, predominantly via store-operated calcium channels. We therefore hypothesized that desensitization by low-dose immunotherapy is associated with reduced influx of calcium ions into lymphocytes. The aim of this study was to test this hypothesis.

Methods

Intracellular lymphocytic calcium ion concentrations were assayed in a total of 47 patients, following incubation with picogram amounts of the test allergens, using a cell-permeable calcium-sensing ratiometric fluorescent dye and fluorescence spectroscopy, both at baseline and following successful provocation neutralization treatment with low-dose immunotherapy.

Results

Low-dose immunotherapy was associated with a reduction in lymphocytic intracellular calcium ion concentration following treatment of: 23 % for metabisulfite sensitivity (p<0.0004); 12 % for salicylate sensitivity (p<0.01); 23 % for benzoate sensitivity (p<0.01); 30 % for formaldehyde sensitivity (p<0.0001); 16 % for sensitivity to petrol exhaust (p<0.003); 16 % for natural gas sensitivity (p<0.001); 13 % for nickel sensitivity (p<0.05); 30 % for sensitivity to organophosphates (p<0.01); and 24 % for sensitivity to nitrosamines (p<0.05).

Conclusions

Low-dose immunotherapy may affect baseline levels of intracellular calcium in lymphocytes, supporting the premise that allergens affect cell signaling in immune cells and provocation neutralization immunotherapy helps to promote more normal immune cell signaling.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: BKP has no conflict of interest to declare. JMcLH and his wife are Directors of Acumen. JAM is Medical Director of Breakspear Medical, which is a family company.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Calderon MA, Demoly P, Gerth van Wijk R, Bousquet J, Sheikh A, Frew A, et al. EAACI: a European declaration on immunotherapy. Designing the future of allergen specific immunotherapy. Clin Transl Allergy. 2012;2:20.10.1186/2045-7022-2-20Search in Google Scholar

2. Yanagida N, Sato S, Asaumi T, Okada Y, Ogura K, Ebisawa M. A single-center, case-control study of low-dose-induction oral immunotherapy with cow’s milk. Int Arch Allergy Immunol. 2015;168:131–137.10.1159/000442157Search in Google Scholar

3. Incorvaia C, Masieri S, Scurati S, Soffia S, Puccinelli P, Frati F. The current role of sublingual immunotherapy in the treatment of allergic rhinitis in adults and children. J Asthma Allergy. 2011;4:13–17.10.2147/JAA.S16632Search in Google Scholar

4. Bahceciler NN, Cobanoglu N. Subcutaneous versus sublingual immunotherapy for allergic rhinitis and/or asthma. Immunotherapy. 2011;3:747–756.10.2217/imt.11.48Search in Google Scholar

5. Bordignon V, Burastero SE. Multiple daily administrations of low-dose sublingual immunotherapy in allergic rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2006;97:158–163.10.1016/S1081-1206(10)60006-3Search in Google Scholar

6. Cabral MD, Paulet PE, Robert V, Gomes B, Renoud ML, Savignac M, et al. Knocking down Cav1 calcium channels implicated in Th2 cell activation prevents experimental asthma. Am J Respir Crit Care Med. 2010;181:1310–1317.10.1164/rccm.200907-1166OCSearch in Google Scholar

7. Vig M, Kinet JP. Calcium signaling in immune cells. Nat Immunol. 2009;10:21–27.10.1038/ni.f.220Search in Google Scholar

8. Wahl M, Lucherini MJ, Gruenstein E. Intracellular Ca2+ measurement with Indo-1 in substrate-attached cells: advantages and special considerations. Cell Calcium. 1990;11:487–500.10.1016/0143-4160(90)90081-5Search in Google Scholar

9. Stefenelli T, Wikman-Coffelt J, Wu ST, Parmley WW. Calcium-dependent fluorescence transients during ventricular fibrillation. Am Heart J. 1990;120:590–597.10.1016/0002-8703(90)90016-QSearch in Google Scholar

10. Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985;260:3440–3450.10.1016/S0021-9258(19)83641-4Search in Google Scholar

11. Gomperts BD, Kramer IM. Tatham PER. Signal transduction, 2nd ed. San Diego, CA: Academic Press, 2009.Search in Google Scholar

12. Zhou Y, Srinivasan P, Razavi S, Seymour S, Meraner P, Gudlur A, et al. Initial activation of STIM1, the regulator of store-operated calcium entry. Nat Struct Mol Biol. 2013;20:973–981.10.1038/nsmb.2625Search in Google Scholar PubMed PubMed Central

Received: 2016-1-23
Accepted: 2017-3-24
Published Online: 2017-4-27
Published in Print: 2017-4-26

© 2017 Walter de Gruyter GmbH, Berlin/Boston