Novel strategies in immunotherapy for allergic diseases

Mohana Rajakulendran; Elizabeth Huiwen Tham; Jian Yi Soh; HP Van Bever

doi:10.5415/apallergy.2018.8.e14

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Rajakulendran, Tham, Soh, and Bever: Novel strategies in immunotherapy for allergic diseases

Current Review

Asia Pac Allergy 2018;8(2):e14.

Published online: 4 April 2018

DOI: https://doi.org/10.5415/apallergy.2018.8.e14

Novel strategies in immunotherapy for allergic diseases

Mohana Rajakulendran^1,^*, Elizabeth Huiwen Tham^1,², Jian Yi Soh^1,², HP Van Bever^1,²

¹Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore 119229

²Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119229

^*Correspondence to Mohana Rajakulendran Department of Paediatrics, National University Health System, Tower Block Level 12, 1E Kent Ridge Road., Singapore 119229. Tel: +65-6772-4112 Fax: +65-6779-7486 E-mail: mohana_rajakulendran@nuhs.edu.sg

Received 30 January 2018 Accepted 2 April 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Conventional immunotherapy (IT) for optimal control of respiratory and food allergies has been fraught with concerns of efficacy, safety, and tolerability. The development of adjuvants to conventional IT has potentially increased the effectiveness and safety of allergen IT, which may translate into improved clinical outcomes and sustained unresponsiveness even after cessation of therapy. Novel strategies incorporating the successful use of adjuvants such as allergoids, immunostimulatory DNA sequences, monoclonal antibodies, carriers, recombinant proteins, and probiotics have now been described in clinical and murine studies. Future approaches may include fungal compounds, parasitic molecules, vitamin D, and traditional Chinese herbs. More robust comparative clinical trials are needed to evaluate the safety, clinical efficacy, and cost effectiveness of various adjuvants in order to determine ideal candidates in disease-specific and allergen-specific models. Other suggested approaches to further optimize outcomes of IT include early introduction of IT during an optimal window period. Alternative routes of administration of IT to optimize delivery and yet minimize potential side effects require further evaluation for safety and efficacy before they can be recommended.

Keywords: Immunotherapy, Allergy immunology, Allergoid, Immunologic stimulation, Monoclonal antibody, Probiotics

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Table 1.

Summary table of novel strategies in immunotherapy (IT)

Novel strategies	Mode of action	Results and recommendations
Allergoids	Extracts which have been modified chemically by substances such as glutaraldehyde or formaldehyde.	Extract dependent with one study showing clinical efficacy [13], but mostly demonstrate both reduced allergenicity and immunogenicity [14, 15, 17].
Immunostimulatory sequences	Induce strong Th1 response.	Small scale clinical studies show improved rhinitis symptom scores [23, 24]. In vitro studies using food sequences also show suppression of allergen-specific IgE levels [25, 26].
Epitope modification	Modification of IgE-binding epitopes to reduce allergenicity.	Protein oligomerization [55-57] and hybrid molecules [59, 63] increase immunogenicity.
Peptide-based immunotherapy	Use of short sequence tolerogenic epitopes which prevent cross-linking of IgE and hence reduce allergenicity.	Positive studies in vivo and mouse models studies [39-41].
Monoclonal antibodies	(1) Anti-IL 4: Suppression of inhibition of FOXP3+ T regulatory cells. (2) Anti-IgE monoclonal antibody: Prevents binding of free IgE to high affinity Fcε R1 IgE receptor.	(1) No additional benefit conferred when used together with SCIT [30]. (2) Improved efficacy with grass and pollen SCIT [32] and cow's milk and peanut OIT [41-43] with improved safety profile.
Carriers	Aluminium hydroxide that induce strong Th2 responses by stimulating antigen-presenting cells. Newer lipid based carriers improve stability and drug delivery, also act as immunomodulators.	Greater immunogenicity and reduced allergenicity in mouse models [21, 48, 49].
Probiotics	Tolerogenic effect via dendritic cell and T-cell responses.	Improved clinical efficacy in grass pollen SLIT [69]. Overall lack of studies.
Earlier timing of introduction	Early and controlled introduction of allergens at an optimally defined timing may induce long-term tolerance starting from an early age in predisposed individuals (87).	The optimal timing for introduction of IT is yet to be determined.
Alternative routes of IT	Administration of allergens via tissues which have a high density of antigen-presenting cells such as via the skin and lymphatics may improve efficacy.	Outcomes of efficacy using the intralymphatic route vary between studies. Some report improved efficacy requiring a shorter duration of treatment [88, 89] while others do not report therapeutic efficacy [90]. Some studies have reported increased adverse effects and recommend dose reductions [91, 92]. Treatment via the epicutaneous route has been shown to be effective but only with high doses of IT [94, 95].

IL, interleukin; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; Fc_Ɛ R1, high-affinity IgE receptor; OIT, oral immunotherapy.

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