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Advances in Immunotherapy of Allergic Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (19 December 2021) | Viewed by 35791

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Special Issue Editors

Dr. Constantinos Pitsios

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Guest Editor

School of Medicine, University of Cyprus, Nicosia, Cyprus
Interests: allergy; allergen immunotherapy; food allergy; eosinophilic esophagitis; clinical immunology; medical physiology
Special Issues, Collections and Topics in MDPI journals

Dr. Caterina Chliva

E-Mail Website
Guest Editor

Allergy Unit “D. Kalogeromitros”, 2nd Department of Dermatology and Venereology, University General Hospital “ATTIKON”, Athens, Greece
Interests: allergic rhinitis; allergens; immunotherapy; asthma; pediatric allergy; food allergy; venom allergy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The continuous advancement of biomedical sciences has offered an extreme boost in improving the diagnosis and therapy of allergic diseases. Allergen immunotherapy remains the only causative treatment of allergic diseases, and is an example of precision medicine offered by allergologists. An accurate diagnosis of respiratory and venom allergies is a necessary tool to choose and provide a “tailor-made” therapy.

In the more than hundred years of practice in immunotherapy, huge advances have been made in developing novel extracts and venoms used as immunotherapy allergens, safety has been increased with the introduction of depot extracts and oral immunotherapy, and new treatment protocols have been approved. The intralymphatic route is also a new promising chapter in allergen immunotherapy. The introduction of immunotherapy for the treatment of food allergy is one of the more recent advances, offering the chance to treat a serious and life-impairing health problem.

This Special Issue aims to collect selected reviews and original data on advances in allergen immunotherapy, in both children and adults. These can include studies on routes of immunotherapy, new protocols, clinical trials of immunotherapy products, and emerging issues on safety and efficacy. The humoral and cellular mechanisms involved in all types of allergy and allergen immunotherapy will also be addressed.

Dr. Constantinos Pitsios
Dr. Caterina Chliva
Guest Editors

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Keywords

allergen immunotherapy
allergic rhinitis
asthma
hymenoptera venom immunotherapy
food allergy
food tolerance induction

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 200 KiB

Open AccessEditorial

Allergen Immunotherapy: New Insights into an Old Treatment

by Constantinos Pitsios

Cells 2022, 11(4), 679; https://doi.org/10.3390/cells11040679 - 15 Feb 2022

Cited by 1 | Viewed by 1510

Abstract

The continuous advancement of biomedical sciences has offered an extreme boost in improving the diagnosis and therapy of allergic diseases [...] Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

Research

Jump to: Editorial, Review

25 pages, 6465 KiB

Open AccessArticle

The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE₂ from Epithelial Cells

by Yen-Ju Lin, Adam Flaczyk, Sonja Wolfheimer, Alexandra Goretzki, Annette Jamin, Andrea Wangorsch, Stefan Vieths, Stephan Scheurer and Stefan Schülke

Cells 2021, 10(12), 3415; https://doi.org/10.3390/cells10123415 - 4 Dec 2021

Cited by 9 | Viewed by 2555

Abstract

Developing new adjuvants/vaccines and better understanding their mode-of-action is an important task. To specifically improve birch pollen allergy treatment, we designed a fusion protein consisting of major birch pollen allergen Betv1 conjugated to the TLR5-ligand flagellin (rFlaA:Betv1). This study investigates the immune-modulatory effects of rFlaA:Betv1 on airway epithelial cells. LA-4 mouse lung epithelial cells were stimulated with rFlaA:Betv1 in the presence/absence of various inhibitors with cytokine- and chemokine secretion quantified by ELISA and activation of intracellular signaling cascades demonstrated by Western blot (WB). Either LA-4 cells or LA-4-derived supernatants were co-cultured with BALB/c bone marrow-derived myeloid dendritic cells (mDCs). Compared to equimolar amounts of flagellin and Betv1 provided as a mixture, rFlaA:Betv1 induced higher secretion of IL-6 and the chemokines CCL2 and CCL20 from LA-4 cells and a pronounced MAPK- and NFκB-activation. Mechanistically, rFlaA:Betv1 was taken up more strongly and the induced cytokine production was inhibited by NFκB-inhibitors, while ERK- and p38-MAPK-inhibitors only suppressed IL-6 and CCL2 secretion. In co-cultures of LA-4 cells with mDCs, rFlaA:Betv1-stimulated LA-4 cells p38-MAPK- and COX2-dependently secreted PGE₂, which modulated DC responses by suppressing pro-inflammatory IL-12 and TNF-α secretion. Taken together, these results contribute to our understanding of the mechanisms underlying the strong immune-modulatory effects of flagellin-containing fusion proteins. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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12 pages, 3239 KiB

Open AccessFeature PaperArticle

Prophylactic and Therapeutic Effects of Oral Immunotherapy on Birch Pollen-Induced Allergic Conjunctivitis in Mice with a Rice-Based Edible Vaccine Expressing a Hypoallergenic Birch Pollen Allergen

by Waka Ishida, Tatsuma Kishimoto, Fumio Takaiwa and Ken Fukuda

Cells 2021, 10(12), 3361; https://doi.org/10.3390/cells10123361 - 30 Nov 2021

Cited by 2 | Viewed by 2752

Abstract

We investigated the prophylactic and therapeutic effects of the oral administration of transgenic rice seeds expressing a hypoallergenic Bet v 1 derivative of allergic birch pollen conjunctivitis in mice. Transgenic rice seed depositing a chimeric molecule called TPC7 (tree pollen chimera 7) created by DNA shuffling of Bet v 1 family sequences from birch, alder and hazel in protein bodies of endosperm was generated. BALB/c mice were sensitized to birch pollen in alum and challenged with pollen in eyedrops. They were fed TPC7 transgenic or non-transgenic (control) rice seeds for 14 d before sensitization (prophylactic protocol) or 17 d after sensitization (therapeutic protocol). The clinical score and number of conjunctival eosinophils were significantly lower in TPC7-fed mice than in the control mice based on both the prophylactic and therapeutic protocols. Serum concentration of allergen-specific IgE did not differ between TPC7-fed and control groups in either protocol. Prophylactic administration of TPC7 downregulated the production of IL-4 and IFN-γ, whereas therapeutic administration of TPC7 upregulated the production of IFN-γ by allergen-stimulated splenocytes. Prophylactic or therapeutic oral administration of transgenic rice expressing TPC7 suppressed birch pollen-induced allergic conjunctivitis in mice. Feeding transgenic rice is a potentially effective approach as an allergen-specific immunotherapy for allergic conjunctivitis. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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20 pages, 2058 KiB

Open AccessFeature PaperArticle

Clinical Relevance and Advantages of Intradermal Test Results in 371 Patients with Allergic Rhinitis, Asthma and/or Otitis Media with Effusion

by David S. Hurst and Alan B. McDaniel

Cells 2021, 10(11), 3224; https://doi.org/10.3390/cells10113224 - 18 Nov 2021

Cited by 7 | Viewed by 2620

Abstract

Background: We evaluated the value of positive intradermal dilution testing (IDT) after negative skin prick tests (SPT) by retrospectively determining allergy immunotherapy (AIT) outcomes. Methods: This private practice, cohort study compared the relative value of SPT vs. IDT in 371 adults and children with suspected manifestations of allergy: chronic allergic rhinitis (AR), asthma and/or chronic otitis media with effusion (OME). The primary outcome measure was symptom resolution following immunotherapy, as determined by symptom severity questionnaires completed by patients before and after AIT. Results: Positive IDT identified 193 (52%) patients who would not otherwise have been diagnosed. IDT detected 3.7-fold more allergens per patient than SPT (8.56 vs. 2.3; p < 0.01). Patients positive only on IDT responded to AIT equally well as those identifiable by SPT, independent of allergen sensitivity (67% by SPT vs. 62% by IDT; p = 0.69, not significantly different). Conclusion: Intradermal titration can identify patients who will benefit from allergy immunotherapy more accurately than SPT. Outcomes analysis in 371 patients shows that IDT doubled their chance of successful treatment with no greater risk of therapeutic failure. Positive IDT, following negative SPT, is clinically relevant and offers superior sensitivity over SPT for detecting allergens clinically relevant to diagnosis of AIT-responsive atopic disease. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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27 pages, 21033 KiB

Open AccessFeature PaperArticle

The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88− and MAPK-Dependent Activation of Glucose Metabolism in Macrophages

by Yen-Ju Lin, Garibald Papp, Csaba Miskey, Anna Fiedler, Alexandra Goretzki, Sonja Wolfheimer, Jennifer Zimmermann, Peter Crauwels, Zoltán Ivics, Ger van Zandbergen, Stefan Vieths, Stephan Scheurer and Stefan Schülke

Cells 2021, 10(10), 2614; https://doi.org/10.3390/cells10102614 - 1 Oct 2021

Cited by 14 | Viewed by 3430

Abstract

TLR5 ligand flagellin-containing fusion proteins are potential vaccine candidates for many diseases. A recombinant fusion protein of flagellin A and the major birch pollen allergen Bet v 1 (rFlaA:Betv1) modulates immune responses in vitro and in vivo. We studied the effects of rFlaA:Betv1 on bone marrow-derived macrophages (BMDMs). BMDMs differentiated from BALB/c, C57BL/6, TLR5^−/−, or MyD88^−/− mice were pre-treated with inhibitors, stimulated with rFlaA:Betv1 or respective controls, and analyzed for activation, cytokine secretion, metabolic state, RNA transcriptome, and modulation of allergen-specific Th2 responses. Stimulation of BMDMs with rFlaA:Betv1 resulted in MyD88-dependent production of IL-1β, IL-6, TNF-α, IL-10, CD69 upregulation, and a pronounced shift towards glycolysis paralleled by activation of MAPK, NFκB, and mTOR signaling. Inhibition of either mTOR (rapamycin) or SAP/JNK-MAPK signaling (SP600125) resulted in dose-dependent metabolic suppression. In BMDM and T cell co-cultures, rFlaA:Betv1 stimulation suppressed rBet v 1-induced IL-5 and IL-13 secretion while inducing IFN-γ production. mRNA-Seq analyses showed HIF-1a, JAK, STAT, phagosome, NLR, NFκB, TNF, TLR, and chemokine signaling to participate in the interplay of cell activation, glycolysis, and immune response. rFlaA:Betv1 strongly activated BMDMs, resulting in MyD88−, MAPK−, and mTOR-dependent enhancement of glucose metabolism. Our results suggest macrophages are important target cells to consider during restauration of allergen tolerance during AIT. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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22 pages, 567 KiB

Open AccessArticle

Indonesia-Based Study of the Clinical and Cost-Saving Benefits of Subcutaneous Allergen Immunotherapy for Children with Allergic Rhinitis in Private Practice

by Anang Endaryanto and Ricardo Adrian Nugraha

Cells 2021, 10(7), 1841; https://doi.org/10.3390/cells10071841 - 20 Jul 2021

Cited by 8 | Viewed by 3707

Abstract

Background: Until now, the cost of allergy treatment in the insured public health care system and the non-insured self-financing private health care system in Indonesia has not been well documented and published, as well as the cost of allergy treatment with subcutaneous immunotherapy. Objective: To evaluate the clinical and cost benefits of allergic rhinitis treatment in children with subcutaneous immunotherapy in a non-insured self-financing private health care system. Methods: A retrospective cohort study conducted from 2015 until 2020 that compared the clinical improvement and health care costs over 18 months in newly diagnosed AR children who received SCIT versus matched AR control subjects who did not receive SCIT, with each group consisting of 1098 subjects. Results: A decrease in sp-HDM-IgE level (kU/mL) from 20.5 + 8.75 kU/mL to 12.1 + 3.07 kU/mL was observed in the SCIT group. To reduce the symptom score of allergic rhinitis by 1.0 with SCIT, it costs IDR 21,753,062.7 per child, and for non-SCIT, it costs IDR 104,147,878.0 per child. Meanwhile, to reduce the medication score (MS) by 1.0 with SCIT, it costs IDR 17,024,138.8, while with non-SCIT, it costs IDR 104,147,878.0. Meanwhile, to lower combination symptoms and medication score (CSMS) by 1.0, with SCIT, it costs IDR 9,550,126.6, while with non-SCIT, it costs IDR 52,073,938.9. Conclusions: In conclusion, this first Indonesia-based study demonstrates substantial health care cost savings associated with SCIT for children with AR in an uninsured private health care system and provides strong evidence for the clinical benefits and cost-savings benefits of AR treatment in children. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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Review

Jump to: Editorial, Research

15 pages, 783 KiB

Open AccessReview

Workup and Clinical Assessment for Allergen Immunotherapy Candidates

by Constantinos Pitsios, Konstantinos Petalas, Anastasia Dimitriou, Konstantinos Parperis, Kyriaki Gerasimidou and Caterina Chliva

Cells 2022, 11(4), 653; https://doi.org/10.3390/cells11040653 - 14 Feb 2022

Cited by 4 | Viewed by 3172

Abstract

Allergen Immunotherapy (AIT) is a well-established, efficient, and safe way to treat respiratory and insect-venom allergies. After determining the diagnosis of the clinically relevant culprit allergen, AIT can be prescribed. However, not all patients are eligible for AIT, since some diseases/conditions represent contraindications to AIT use, as described in several guidelines. Allergists are often preoccupied on whether an extensive workup should be ordered in apparently healthy AIT candidates in order to detect contra-indicated diseases and conditions. These preoccupations often arise from clinical, ethical and legal issues. The aim of this article is to suggest an approach to the workup and assessment of the presence of any underlying diseases/conditions in patients with no case history before the start of AIT. Notably, there is a lack of published studies on the appropriate evaluation of AIT candidates, with no globally accepted guidelines. It appears that Allergists are mostly deciding based on their AIT training, as well as their clinical experience. Guidance is based mainly on experts’ opinions; the suggested preliminary workup can be divided into mandatory and optional testing. The evaluation for possible underlying neoplastic, autoimmune, and cardiovascular diseases, primary and acquired immunodeficiencies and pregnancy, might be helpful but only in subjects for whom the history and clinical examination raise suspicion of these conditions. A workup without any reasonable correlation with potential contraindications is useless. In conclusion, the evaluation of each individual candidate for possible medical conditions should be determined on a case-by-case basis. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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22 pages, 2115 KiB

Open AccessFeature PaperReview

Allergen Immunotherapy: Current and Future Trends

by Gandhi F. Pavón-Romero, Maria Itzel Parra-Vargas, Fernando Ramírez-Jiménez, Esmeralda Melgoza-Ruiz, Nancy H. Serrano-Pérez and Luis M. Teran

Cells 2022, 11(2), 212; https://doi.org/10.3390/cells11020212 - 8 Jan 2022

Cited by 37 | Viewed by 9844

Abstract

Allergen immunotherapy (AIT) is the sole disease-modifying treatment for allergic rhinitis; it prevents rhinitis from progressing to asthma and lowers medication use. AIT against mites, insect venom, and certain kinds of pollen is effective. The mechanism of action of AIT is based on inducing immunological tolerance characterized by increased IL-10, TGF-β, and IgG4 levels and Treg cell counts. However, AIT requires prolonged schemes of administration and is sometimes associated with adverse reactions. Over the last decade, novel forms of AIT have been developed, focused on better allergen identification, structural modifications to preserve epitopes for B or T cells, post-traductional alteration through chemical processes, and the addition of adjuvants. These modified allergens induce clinical-immunological effects similar to those mentioned above, increasing the tolerance to other related allergens but with fewer side effects. Clinical studies have shown that molecular AIT is efficient in treating grass and birch allergies. This article reviews the possibility of a new AIT to improve the treatment of allergic illness. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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12 pages, 1173 KiB

Open AccessReview

Hymenoptera Venom Immunotherapy: Immune Mechanisms of Induced Protection and Tolerance

by Ajda Demšar Luzar, Peter Korošec, Mitja Košnik, Mihaela Zidarn and Matija Rijavec

Cells 2021, 10(7), 1575; https://doi.org/10.3390/cells10071575 - 22 Jun 2021

Cited by 17 | Viewed by 4947

Abstract

Hymenoptera venom allergy is one of the most severe allergic diseases, with a considerable prevalence of anaphylactic reaction, making it potentially lethal. In this review, we provide an overview of the current knowledge and recent findings in understanding induced immune mechanisms during different phases of venom immunotherapy. We focus on protection mechanisms that occur early, during the build-up phase, and on the immune tolerance, which occurs later, during and after Hymenoptera venom immunotherapy. The short-term protection seems to be established by the early desensitization of mast cells and basophils, which plays a crucial role in preventing anaphylaxis during the build-up phase of treatment. The early generation of blocking IgG antibodies seems to be one of the main reasons for the lower activation of effector cells. Long-term tolerance is reached after at least three years of venom immunotherapy. A decrease in basophil responsiveness correlates with tolerated sting challenge. Furthermore, the persistent decline in IgE levels and, by monitoring the cytokine profiles, a shift from a Th2 to Th1 immune response, can be observed. In addition, the generation of regulatory T and B cells has proven to be essential for inducing allergen tolerance. Most studies on the mechanisms and effectiveness data have been obtained during venom immunotherapy (VIT). Despite the high success rate of VIT, allergen tolerance may not persist for a prolonged time. There is not much known about immune mechanisms that assure long-term tolerance post-therapy. Full article

(This article belongs to the Special Issue Advances in Immunotherapy of Allergic Diseases)

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