A preseason booster prolongs the increase of allergen specific IgG4 levels, after basic allergen intralymphatic immunotherapy, against grass pollen seasonal allergy

Dan Weinfeld, Ulla Westin, Laila Hellkvist, Ulf-Henrik Mellqvist, Ingvar Jacobsson, Lars-Olaf Cardell, Dan Weinfeld, Ulla Westin, Laila Hellkvist, Ulf-Henrik Mellqvist, Ingvar Jacobsson, Lars-Olaf Cardell

Abstract

Background: Allergen specific IgG4 levels have been monitored as a surrogate marker for the tolerance inducing effect of subcutaneous immunotherapy (SCIT) in many studies. Its accuracy at group level has been well established, but IgG4 has not yet found its place in the daily care of immunotherapy patients.

Methods: Intralymphatic immunotherapy (ILIT) is a novel route for allergy vaccination against pollen allergy, where an ultrasound-guided injection of 1000 SQ-U Alutard is given directly into a groin lymph node. The suggested standard dosing so far has been one injection with 4 weeks in-between. In total 3000 SQ-U with the treatment completed in 2 months. IgG4 was measured with Immulite technique and rhinoconjunctivitis symptoms were estimated with daily online questionnaires. Mann-Whitney U-test and Wilcoxon Signed Rank test were applied for comparisons between groups and within groups, respectively.

Results: The present study demonstrates that a single, preseason ILIT booster of 1000 SQ-U Alutard 5-grasses®, re-increases the allergen specific timothy-IgG4 levels, in patients already treated with ILIT before the previous pollen season. It also shows the feasibility of the ILIT-route for allergy vaccination of rhinitis patients, with or without concomitant asthma, with low degree of side effects and reconfirms high and sustained patient satisfaction.

Conclusions: It is tempting to suggest that the allergen specific IgG4 levels can be used to build an intuitive algorithm for future clinical guidance of ILIT patients.Trial registration Is Intralymphatic Allergen Immunotherapy Effective and Safe?, ClinicalTrials.gov Identifier NCT04210193. Registered 24 December 2019-Retrospectively registered, https://ichgcp.net/clinical-trials-registry/NCT04210193?term=NCT04210193&draw=2&rank=1.

Keywords: Asthma; Grass pollen allergy rhinoconjunctivitis; IgG4; Intralymphatic immunotherapy; Randomized booster.

Conflict of interest statement

Competing interestsNot applicable.

© The Author(s) 2020.

Figures

Fig. 1
Fig. 1
Grass allergic patients were treated with ILIT and then randomized double blind to an active or placebo ILIT booster dose after 1 year. Questionnaires were completed during the pollen seasons and blood samples for IgG4 measurements were obtained at several occasions
Fig. 2
Fig. 2
Specific IgG4-timothy by active booster (n = 6)/Placebo booster (n = 6) and changes from Jan-15 (baseline) and from Dec-15 (1 month pre-booster). All patients injected monthly 3 times from Jan 2015. Blue circles represent individuals who received a booster (4th) active injection Jan 2016. Red triangles received placebo (4th) injection in Jan 2016. Lines represents median values. * shows significant difference between active booster/placebo booster (p 

References

    1. Bousquet J, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen) Allergy. 2008;63(Suppl 86):8–160. doi: 10.1111/j.1398-9995.2007.01620.x.
    1. Noon L. Profylactic inoculation against hay fever. Lancet. 1911;177:1572–1573. doi: 10.1016/S0140-6736(00)78276-6.
    1. Passalacqua G, Canonica GW. Allergen immunotherapy: history and future developments. Immunol Allergy Clin N Am. 2016;36(1):1–12. doi: 10.1016/j.iac.2015.08.001.
    1. Durham SR, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341(7):468–475. doi: 10.1056/NEJM199908123410702.
    1. Mahler V, et al. Understanding differences in allergen immunotherapy products and practices in North America and Europe. J Allergy Clin Immunol. 2019;143(3):813–828. doi: 10.1016/j.jaci.2019.01.024.
    1. Senti G, et al. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci USA. 2008;105(46):17908–17912. doi: 10.1073/pnas.0803725105.
    1. Hylander T, et al. Intralymphatic immunotherapy of pollen-induced rhinoconjunctivitis: a double-blind placebo-controlled trial. Respir Res. 2016;17:10. doi: 10.1186/s12931-016-0324-9.
    1. Hylander T, et al. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis. J Allergy Clin Immunol. 2013;131(2):412–420. doi: 10.1016/j.jaci.2012.10.056.
    1. Witten M, et al. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy? J Allergy Clin Immunol. 2013;132(5):1248–1252. doi: 10.1016/j.jaci.2013.07.033.
    1. Patterson AM, et al. Three-injection intralymphatic immunotherapy in adolescents and young adults with grass pollen rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2016;116(2):168–170. doi: 10.1016/j.anai.2015.11.010.
    1. Schmid JM, et al. Intralymphatic immunotherapy induces allergen specific plasmablasts and increases tolerance to skin prick testing in a pilot study. Clin Transl Allergy. 2016;6:19. doi: 10.1186/s13601-016-0107-x.
    1. Hellkvist L, et al. Intralymphatic immunotherapy with 2 concomitant allergens, birch and grass: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2018;142(4):1338–1341. doi: 10.1016/j.jaci.2018.05.030.
    1. Senti G, et al. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012;129(5):1290–1296. doi: 10.1016/j.jaci.2012.02.026.
    1. Lee SP, et al. A pilot study of intralymphatic immunotherapy for house dust mite, cat, and dog allergies. Allergy Asthma Immunol Res. 2017;9(3):272–277. doi: 10.4168/aair.2017.9.3.272.
    1. Lee SP, et al. Intralymphatic immunotherapy alleviates allergic symptoms during allergen exposure in daily life. Allergy Asthma Immunol Res. 2018;10(2):180–181. doi: 10.4168/aair.2018.10.2.180.
    1. Kim ST, et al. Allergen-specific intralymphatic immunotherapy in human and animal studies. Asia Pac Allergy. 2017;7(3):131–137. doi: 10.5415/apallergy.2017.7.3.131.
    1. Senti G, et al. Intralymphatic Immunotherapy: update and Unmet Needs. Int Arch Allergy Immunol. 2019;178(2):141–149. doi: 10.1159/000493647.
    1. Hellkvist,L High dose grass pollen intralymphatic immunotherapy: Two RDBPC trials question the benefit of dose increases. (Submitted 2020).
    1. Ahlbeck L, et al. Intralymphatic allergen immunotherapy against pollen allergy: a 3-year open follow-up study of 10 patients. Ann Allergy Asthma Immunol. 2018;121(5):626–627. doi: 10.1016/j.anai.2018.07.010.
    1. Kundig TM, et al. Intralymphatic immunotherapy: time interval between injections is essential. J Allergy Clin Immunol. 2014;133(3):930–931. doi: 10.1016/j.jaci.2013.11.036.
    1. Ahlbeck L. Intralymphatic allergen immunotherapy against birch and grass pollen allergy. A 3-year double blind randomized clinical trial of 72 patients, in Oral Abstract Session EAACI Congress Lisbon. 2019.
    1. Hoffmann HJSS, Schmid JM, Skjold T, Graumann O. Intralymphatic allergen immunotherapy is safe and reduces symptoms and use of rescue medication in grass pollen allergy. A double blind randomized placebo controlled study. Non published observations.
    1. Shamji MH, et al. Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper. Allergy. 2017;72(8):1156–1173. doi: 10.1111/all.13138.
    1. Schmid JM, et al. Pretreatment IgE sensitization patterns determine the molecular profile of the IgG4 response during updosing of subcutaneous immunotherapy with timothy grass pollen extract. J Allergy Clin Immunol. 2016;137(2):562–570. doi: 10.1016/j.jaci.2015.05.023.
    1. Gehlhar K, et al. Monitoring allergen immunotherapy of pollen-allergic patients: the ratio of allergen-specific IgG4 to IgG1 correlates with clinical outcome. Clin Exp Allergy. 1999;29(4):497–506. doi: 10.1046/j.1365-2222.1999.00525.x.
    1. Scadding GW, et al. Effect of 2 years of treatment with sublingual grass pollen immunotherapy on nasal response to allergen challenge at 3 years among patients with moderate to severe seasonal allergic rhinitis: The GRASS randomized clinical trial. JAMA. 2017;317(6):615–625. doi: 10.1001/jama.2016.21040.
    1. Renand A, et al. Synchronous immune alterations mirror clinical response during allergen immunotherapy. J Allergy Clin Immunol. 2018;141(5):1750–1760. doi: 10.1016/j.jaci.2017.09.041.
    1. Aalberse R. The role of IgG antibodies in allergy and immunotherapy. Allergy. 2011;66(Suppl 95):28–30. doi: 10.1111/j.1398-9995.2011.02628.x.
    1. Aalberse RC, Schuurman J. IgG4 breaking the rules. Immunology. 2002;105(1):9–19. doi: 10.1046/j.0019-2805.2001.01341.x.
    1. Aalberse RC, et al. Immunoglobulin G4: an odd antibody. Clin Exp Allergy. 2009;39(4):469–477. doi: 10.1111/j.1365-2222.2009.03207.x.
    1. van der Neut Kolfschoten M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317(5844):1554–1557. doi: 10.1126/science.1144603.
    1. Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy Clin Immunol. 2017;140(6):1485–1498. doi: 10.1016/j.jaci.2017.10.010.
    1. Shamji MH, Durham SR. Mechanisms of immunotherapy to aeroallergens. Clin Exp Allergy. 2011;41(9):1235–1246. doi: 10.1111/j.1365-2222.2011.03804.x.
    1. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J. 2015;8(1):17. doi: 10.1186/s40413-015-0063-2.
    1. Shamji MH, et al. Nasal allergen-neutralizing IgG4 antibodies block IgE-mediated responses: novel biomarker of subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol. 2019;143(3):1067–1076. doi: 10.1016/j.jaci.2018.09.039.
    1. van de Veen W, Akdis M. Role of IgG4 in IgE-mediated allergic responses. J Allergy Clin Immunol. 2016;138(5):1434–1435. doi: 10.1016/j.jaci.2016.07.022.
    1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539–551. doi: 10.1056/NEJMra1104650.
    1. Jarkvist J, et al. Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection. Allergy. 2020;75(1):169–177. doi: 10.1111/all.13980.
    1. Brandstrom J, et al. Individually dosed omalizumab facilitates peanut oral immunotherapy in peanut allergic adolescents. Clin Exp Allergy. 2019;49(10):1328–1341. doi: 10.1111/cea.13469.
    1. Moingeon P. Biomarkers for allergen immunotherapy: a “panoromic” view. Immunol Allergy Clin N Am. 2016;36(1):161–179. doi: 10.1016/j.iac.2015.08.004.
    1. James LK, et al. Allergen specificity of IgG(4)-expressing B cells in patients with grass pollen allergy undergoing immunotherapy. J Allergy Clin Immunol. 2012;130(3):663–670. doi: 10.1016/j.jaci.2012.04.006.
    1. van de Veen W, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013;131(4):1204–1212. doi: 10.1016/j.jaci.2013.01.014.
    1. Shamji MH, et al. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy. 2012;67(2):217–226. doi: 10.1111/j.1398-9995.2011.02745.x.
    1. Pilette C, et al. Grass pollen immunotherapy induces an allergen-specific IgA2 antibody response associated with mucosal TGF-beta expression. J Immunol. 2007;178(7):4658–4666. doi: 10.4049/jimmunol.178.7.4658.
    1. Schmid JM, et al. Early improvement in basophil sensitivity predicts symptom relief with grass pollen immunotherapy. J Allergy Clin Immunol. 2014;134(3):741–744. doi: 10.1016/j.jaci.2014.04.029.
    1. Shamji MH, et al. Basophil expression of diamine oxidase: a novel biomarker of allergen immunotherapy response. J Allergy Clin Immunol. 2015;135(4):913–921. doi: 10.1016/j.jaci.2014.09.049.
    1. Arzt L, et al. Immunological differences between insect venom-allergic patients with and without immunotherapy and asymptomatically sensitized subjects. Allergy. 2018;73(6):1223–1231. doi: 10.1111/all.13368.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe