Contribution of Kazal-Like Domains of the Serine Protease Inhibitor-1 from Toxoplasma gondii in Asthma Therapeutic Vaccination Effectiveness

<b><i>Background:</i></b> We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. <b><i>Objectives:</i></b> In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. <b><i>Methods:</i></b> BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. <b><i>Results:</i></b> Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. <b><i>Conclusions:</i></b> Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.

HLA-G in Allergy: Does It Play an Immunoregulatory Role?

Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.

TGF-β1 Drives Inflammatory Th Cell But Not Treg Cell Compartment Upon Allergen Exposure

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 (Tgfbr2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9, and reduced Tregs cells, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs cells.

Role of periostin in evaluating the responsiveness of allergic patients to allergen-specific immunotherapy

Objectives: Allergen-specific immunotherapy (AIT) has been considered the most effective treatment for IgE mediated allergies, especially respiratory allergies. Several biomarkers have been developed to evaluate the clinical efficacy of AIT, yet none of them have been thoroughly validated. So our objective here is to investigate the usefulness of periostin as a biomaker for monitoring the efficacy of allergen immunotherapy. Materials and methods: This study included 46 healthy non-atopic volunteers and 46 patients with allergic rhinitis (AR). They were sensitized only to date palm pollen. The participants were tested by skin prick test and total serum IgE levels were measured. Serum samples were collected from healthy subjects and allergic patients before and after the one-year AIT. Serum levels of periostin, eotaxin, and sIL-2R were estimated by ELISA. Symptom scores in the allergic patients were also evaluated before and after completing one year AIT. Results: There is a significant increase in serum levels of IgE, periostin, sIL-2R, and eotaxin in allergic patients as compared to healthy controls. Symptom scores, sIL-2R and serum periostin levels were significantly decreased after one-year AIT in AR patients. Conclusion: Periostin can be used as a biomarker to evaluate AIT efficacy in AR patients. Bangladesh Journal of Medical Science Vol. 21(1) 2022 Page : 184-190

Association between the type of allergen and T-helper 2 mediated inflammation in allergic reactions: a systematic review and a meta-analysis

Objectives: To determine whether the levels of T-helper (TH) 2 cytokines (interleukin (IL)-4 and IL-5) in allergic reactions are allergen dependent and evaluate the impact of various treatment strategies on the levels of these cytokines.Methods: The PubMed search engine was used from inception until January 2021. The random-effects residual maximum likelihood model was performed, and effect sizes were estimated using the Hedge’s g statistic. All data analysis was performed using STATA 16.0 (StataCorp LP, TX, USA). Results: Fourteen studies reporting on 794 participants were included in this study. House dust mite was associated with eliciting a stronger immune response mediated by both IL-4 and IL-5 when compared to pollen. Whereas a mixture of house dust mite and pollen was associated with IL-4-weighted inflammation. Comparisons of IL-4 and IL-5 levels amongst the allergens showed significant differences. The treatment with anti-corticosteroids or allergen-specific immunotherapy was effective in normalising the TH2 responses and alleviating allergy symptoms.Conclusion: TH2-mediated inflammation in allergic reactions is allergen-dependent. Therefore, the type of allergen should be considered when using cytokine-targeting biologics in allergic reactions.

Effectiveness and safety of oral lactococci-based vaccine encoding triple common allergens to prevent airway allergy in mice

Allergic airway disease is the most common chronic airway inflammatory disorder in developed countries. House dust mite, cockroach, and mold are the leading allergens in most tropical and subtropical countries, including Taiwan. As allergen avoidance is difficult for patients allergic to these perennial indoor allergens, allergen-specific immunotherapy (ASIT) is the only available allergen-specific and disease-modifying treatment. However, for patients sensitized to multiple allergens, ASIT using each corresponding allergen is cumbersome. In the present study, we developed a recombinant L. lactis vaccine against the three most common indoor aeroallergens and investigated its effectiveness for preventing respiratory allergy and safety in mice. Three recombinant clones of Der p 2 (mite), Per a 2 (roach), and Cla c 14 (mold) were constructed individually in pNZ8149 vector and then electroporated into host strain L.lactis NZ3900. BALB/c mice were fed with the triple vaccine 5 times per week for 4 weeks prior to sensitization. The effectiveness and safety profile were then determined. Oral administration of the triple vaccine significantly alleviated allergen-induced airway hyper-responsiveness in the vaccinated mice. The allergen-specific IgG2a was upregulated. IL-4 and IL-13 mRNA expressions as well as inflammatory cell infiltration in the lungs decreased significantly in the vaccinated groups. No body weight loss or abnormal findings in the liver and kidneys were found in any of the groups of mice. This is the first report to describe a triple-aeroallergen vaccine using a food-grade lactococcal expression system. We developed a convenient oral delivery system and intend to extend this research to develop a vaccination that can be self-administered at home by patients.

Preparation and Characterization of a Glycyrrhizic Acid-Based Drug Delivery System for Allergen-Specific Immunotherapy

The most effective method of treating allergic diseases, aimed not at relieving symptoms, but at eliminating the cause of the disease, is allergen-specific immunotherapy (AIT). To reduce the risk of side effects and improve the delivery of allergens to the mucosa, various delivery systems, such as liposomes, dendrimers, nanoparticles, etc., can be used. To date, there are data on the creation of delivery systems based on glycyrrhizic acid (GA) and its derivatives, but such a delivery system has not been used for allergen-specific therapy until now. It is also known that GA has an anti-inflammatory effect, shifts the balance towards Th1, and increases the number of Treg cells, meaning that it could potentially enhance the anti-allergic effect of AIT and reduce the risk of unwanted side effects. Thus, the study of the immunomodulatory effect of the supramolecular complexes (micelles) of GA with extracts of allergens holds promise for the development of new drugs for AIT.

Fexofenadine HCl Microspheres – Can it be the First Line therapy for Allergic Disorders ?

Fexofenadine HCl is a second-generation antihistamine which is commonly used for allergic disorders. But it has low bioavailability. Intranasal corticosteroids (INCs) and Immunotherapy and Allergen Specific Immunotherapy (ASIT) are now commonly being suggested for the treatment of allergic disorders. Despite the fact that current treatment alternatives have been in use for decades, patient quality of life has remained static. The treatment options are not much explored for their respective adverse effects. Therefore, they are in desperate need of research. Fexofenadine HCl is available in the form of a suspension, tablet, or capsule. In our current study, we have explored whether microspheres can be the perfect dosage form of Fexofenadine HCl to treat allergic disorders considering the pharmacokinetics of the drug, available dosage forms options and the probable side effects of the current therapies.

Standardized Quantitative Evaluation of Clinical Effectiveness and Side Effect Profile of Subcutaneous and Sublingual Allergen-Specific Immunotherapy in Children: A 5-Year Single Center Experience

Objective: Allergen-specific immunotherapy (allergen-SIT) is a treatment method with variable efficacy in allergic diseases. This study aimed to investigate the effectiveness of allergen immunotherapy, frequency of LRs and SRs and variables affecting these parameters in patients who underwent allergen-SIT. Materials and Methods: In this study, the recorded data of 81 patients, who received subcutaneous (SCIT) or sublingual (SLIT) allergen immunotherapy for respiratory allergic diseases between 2014 and 2019, were analyzed. In asthma and/or allergic rhinoconjunctivitis (ARC) patients, the effectiveness of treatment was evaluated by analysing the change rates in disease symptom, medication and combined scores (symptom + medication) and visual analog score (VAS). Treatment success was defined by the degree of decrease in scores as; high response above 50%; low response between 20-50%; and failure <20%.Results: The mean age of allergen-SIT initiation was 11.4± 3.1 years. Diagnostic distributions of the patients were asthma (± ARC) in 64.2%, and ARC (without asthma) in 35.8%. The mode of allergen-SIT was SCIT in 77.8% (65% asthma and 35% ARC) and SLIT in 22.2% (61.1% asthma and 38.9% ARC). The main allergens used in allergen-SIT were mite (79%), grass-grain pollen (33.3%), alternaria (9.9%) and olea (8.6%). There was a significant decrease in symptoms, medication, combined and VAS scores in the asthma and ARC groups (p <0.0001), when end-SCIT values were compared to baseline. SLIT also resulted in significant decreases in these scores except asthma medication score. Among the asthma patients the rate of high-responders was 88.8% by SCIT and 50% by SLIT, according to combined asthma score. Among the ARC (without asthma) patients the rate of high-responders was 100% for both SCIT and SLIT. SCIT resulted in local (LR) and systemic side effects (SR) in 18% and 0.6% (all Grade I and Grade II) of the total injections performed. A high number of total injections was significantly associated with higher LR and SR rates. While LR was observed in 16.6% of the patients who underwent SLIT, no systemic reaction was found in any of the patients. Conclusion: SCIT was highly successful in the treatment of asthma and ARC in terms of the degree of therapeutic response. SLIT resulted in a high rate of good response in ARC patients, but a lower response degree in asthmatic patients. Systemic side effects were very low as a result of close risk monitoring and the dose adjustments performed. Keywords: Allergen-specific immunotherapy, SCIT, SLIT, efficacy, symptom score, medication score, visual analog score, side effects