Therapy Of Allergic Diseases Research Articles

Allosteric inhibition of IgE–FcεRI interactions by simultaneous targeting of IgE F(ab’)2 epitopes

Immunoglobulin E (IgE) plays pivotal roles in allergic diseases through interaction with a high-affinity receptor (FcεRI). We established that Fab fragments of anti-IgE antibodies (HMK-12 Fab) rapidly dissociate preformed IgE-FcεRI complexes in a temperature-dependent manner and inhibit IgE-mediated anaphylactic reactions, even after allergen challenge. X-ray crystallographic studies revealed that HMK-12 Fab interacts with each of two equivalent epitopes on the Cε2 homodimer domain involved in IgE F(ab’)2. Consequently, HMK-12 Fab-mediated targeting of Cε2 reduced the binding affinity of Fc domains and resulted in rapid removal of IgE from the receptor complex. This unexpected finding of allosteric inhibition of IgE-FcεRI interactions by simultaneous targeting of two epitope sites on the Cε2 homodimer domain of IgE F(ab’)2 may have implications for the development of novel therapies for allergic disease.

Basics in diagnostics and therapy of allergic diseases for ENT consultations

Allergies play a pivotal role in the daily practice of ENT specialists. Allergic symptoms induced by inhalant allergens are widespread in the population and can manifest through a wide range of symptoms, including rhinorrhea, sneezing, conjunctival redness, cough and dyspnea. Inconsistent diagnosis and treatment of allergic conditions can lead to reduced quality of life, decreased work performance, and socioeconomically significant secondary diseases. In addition to the medical history, the skin prick test and serological IgE diagnostics are the most important diagnostic procedure for detecting type-I allergies. To clarify clinical relevance, molecular diagnostics and nasal provocation testing may be employed. The key to effective treatment lies in a comprehensive allergological diagnosis coupled with a detailed patient history. General treatment recommendations such as allergen avoidance and nasal irrigation should complement pharmacological therapy. In the treatment of allergic rhinitis topical steroids are first line treatment options. The primary goal of treatment is symptom control, and if control is insufficient, causal therapy through specific allergen immunotherapy is recommended. Challenges in the ENT clinic involve selecting the necessary diagnostics and appropriate, effective treatments. Hence, using diagnostic and treatment algorithms, as well as standardized patient history questionnaires, can serve as invaluable tools in daily patient interactions, especially considering limited time availability.

Dupilumab in the treatment of severe adopic dermatitis and respiratory allergy: a case report

The use of biological targeted therapy for allergic diseases has significantly increased the effectiveness of the treatment of patients with atopic dermatitis, bronchial asthma, and combined allergopathology. Dupilumab, a monoclonal antibody drug that blocks signaling from IL-4 and IL-13, is one of the options for biological therapy aimed at modifying the Th2 immune response. The article discusses current ideas about the pathogenesis of allergic Th2-dependent inflammation, about the key mechanisms of the formation of atopic dermatosis and its role in inducing the progressive course of atopy. A clinical example of successful treatment of an 8-year-old child with severe atopic dermatitis, moderate partially controlled bronchial asthma, allergic rhinitis, and multisensitization to food and pollen allergens is given. The use of biological targeted therapy with dupilumab made it possible to achieve sustainable remission in the course of atopic dermatitis and bronchial asthma. The SCORAD index, which was 66.8 points before dupilumab treatment, decreased to 8.9 points. Immunobiological therapy with an IL-4Rα inhibitor, dupilumab, is indicated for patients with moderate to severe allergic diseases when it is not possible to achieve adequate control with standard treatment methods. The presented clinical case of the use of the drug contributes to the study of the clinical efficacy and safety of dupilumab during its long-term use.

Fecal Microbiota Transplantation Alleviates Allergic Rhinitis via CD4+ T Cell Modulation Through Gut Microbiota Restoration.

Allergic rhinitis (AR) is an allergic condition of the upper respiratory tract with a complex pathogenesis, including epithelial barrier disruption, immune regulation, and gut microbiota, which is not yet fully understood. Gut microbiota is closely linked to allergic diseases, including AR. Fecal microbiota transplantation (FMT) has recently been recognized as a potentially effective therapy for allergic diseases. However, the efficacy and mechanism of action of FMT in AR remain unknown. Herein, we aimed to observe the implications of gut microbiota on epithelial barrier function and T cell homeostasis, as well as the effect of FMT in AR, using the ovalbumin (OVA)-induced AR mice. The intestinal microbiota of recipient mice was cleared using an antibiotic cocktail; thereafter, FMT was performed. Subsequently, the nasal symptom scores and histopathological features of colon and nasal mucosa tissues of mice were monitored, and serum OVA-sIgE and cytokines of IL-4, IFNγ, IL-17A, and IL-10 cytokine concentrations were examined. Thereafter, tight junction protein and CD4+ T cell-related transcription factor and cytokine expressions were observed in the colon and nasal mucosa, and changes in the expression of PI3K/AKT/mTOR and NFκB signaling pathway were detected by WB assay in each group. Fecal DNA was extracted from the four mice groups for high-throughput 16S rRNA sequencing. FMT ameliorated nasal symptoms and reduced nasal mucosal inflammation in AR mice. Moreover, according to 16S rRNA sequencing, FMT restored the disordered gut microbiota in AR mice. Following FMT, ZO-1 and claudin-1 and Th1/Th2/Th17-related transcription factor and cytokine expressions were upregulated, whereas Treg cell-related Foxp3 and IL-10 expressions were downregulated. Mechanistic studies have revealed that FMT also inhibited PI3K/AKT/mTOR and NF-κB pathway protein phosphorylation in AR mouse tissues. FMT alleviates allergic inflammation in AR by repairing the epithelial barrier and modulating CD4+ T cell balance and exerts anti-inflammatory effects through the PI3K/AKT/mTOR and NF-κB signaling pathways. Moreover, gut microbiota disorders are involved in AR pathogenesis. Disturbed gut microbiota causes an altered immune-inflammatory state in mice and increases susceptibility to AR. This study suggested the regulatory role of the gut-nose axis in the pathogenesis of AR is an emerging field, which provides novel directions and ideas for the treatment of AR.

Pharmacoequity in Allergy-Immunology: Disparities in Access to Medications for Allergic Diseases and Proposed Solutions in the United States and Globally

Pharmacoequity is the principle that individuals should have access to high-quality medications regardless of race and ethnicity, socioeconomic status, or availability of resources. In this review, we summarize access to therapeutics for allergic diseases in the United States and other selected countries. We focus on domains of health care access (health insurance coverage, medication availability, and specialist access) as well as system-level factors and clinician- and patient-level factors such as interpersonal racism and cultural beliefs, and how they can affect timely access to appropriate therapy for allergic diseases. Finally, we propose how pharmacoequity in allergy-immunology can be achieved by highlighting solutions to factors limiting access to medications for allergic diseases, and identify potential future research directions.

Preclinical evaluation of alternatives to oral immunotherapy for food allergies.

The increasing food allergy incidence has led to significant interest in developing therapies for allergic diseases. Oral allergen-specific immunotherapy (OIT) is a recently FDA-approved therapeutic to treat peanut allergies. OIT utilizes daily allergen dosing to reduce allergic reactions to peanuts. However, there is diminished enthusiasm for daily OIT, potentially due to the strict regimen required to induce desensitization and the risks of severe adverse events. Thus, there remains a need for safe and effective food allergy treatments that are well-received by allergic individuals. Preclinical research studies investigate methods to induce allergen desensitization in animals and support clinical studies that address the limitations of current food allergy OIT. Because allergic reactions are triggered by allergen doses above an individual's activation threshold, immunotherapy regimens that induce allergen desensitization with lower allergen doses or without the requirement of daily administrations may expand the use of food allergy immunotherapy. Administering allergen immunotherapy by alternative routes is a strategy to induce desensitization using lower allergen doses than OIT. Several animal models have evaluated oral, sublingual, epicutaneous, and intranasal immunotherapy routes to treat food allergies. Each immunotherapy route may require different allergen doses, formulations, and treatment schedules to induce desensitization. This article will discuss scientific findings from food allergy immunotherapy animal studies that utilize various immunotherapy routes to induce allergen desensitization to support future clinical studies that enhance the safety and efficacy of allergen immunotherapy to treat food allergies.

AIT in pediatric allergology: Opportunities and difficulties on the home stretch of the Therapy Allergen Ordinance.

Allergen immunotherapy (AIT) is the only causal therapy for allergic diseases and therefore particularly important. Allergen preparations have been classified as medicinal products since 1989 (Directive 89/342/EEC) and were taken over into Directive 2001/83/EC in 2001. In addition, in 2008 the Therapy Allergen Ordinance (TAO) came into force to stricter regulate the exception for named patient products (NPP) by exclusion of common therapy allergens from the exception to be marketed as NPP. The TAO regulates the requirements for testing safety and efficacy for these common therapy allergens. Due to the long transitional provisions, the last deadlines for solving clinical shortcomings will end in 2026. The advantage of this regulation is that the market for common allergens has been cleared of products without proof of efficacy, and new preparations with an optimal dose range are developed through dose-finding studies. The demand for long-term pediatric studies has been outlined by the standard Pediatric Investigation Plan (PIP) on allergen products from the Pediatric Committee of the EMA (PDCO). This is particularly problematic, as it is foreseeable that recruitment of patients will be limited and ethical problems arise from the prolonged use of placebo. Furthermore, many newly approved preparations will not be used in pediatrics for the foreseeable future, as no marketing authorization has yet been granted for this age group. This will result in a serious supply gap for children.

Heterogeneity, subsets, and plasticity of T follicular helper cells in allergy

Antibody responses are critical for protection against pathogens. However, diseases such as allergic rhinitis or food allergy result from aberrant production of IgE antibodies against otherwise innocuous environmental antigens. The production of allergen-specific IgE requires interaction between B cells and CD4⁺ T cells, and a granular understanding of these interactions is required to develop novel therapies for allergic disease. CD4⁺ T cells are exceptionally heterogeneous in their transcriptional, epigenetic, and proteomic profiles, which poses significant challenges when attempting to define subsets relevant to the study of allergy among a continuum of cells. Defining subsets such as the T follicular helper (T_FH) cell cluster provides a shorthand to understand the functions of CD4⁺ T cells in antibody production and supports mechanistic experimentation for hypothesis-driven discovery. With a focus on allergic disease, this Rostrum article broadly discusses heterogeneity among CD4⁺ T cells and provides a rationale for subdividing T_FH cells into both functional and cytokine-skewed subsets. Further, it highlights the plasticity demonstrated by T_FH cells during the primary response and after recall, and it explores the possibility of harnessing this plasticity to reprogram immunity for therapeutic benefit in allergic disease.

Neuroimmunology and Allergic Disease

The prevalence of allergic diseases is rising globally, inducing heavy quality of life and economic burdens. Allergic reactions are mediated by the complex bi-directional cross-talk between immune and nervous systems that we are only beginning to understand. Here, we discuss our current understanding of the molecular mechanisms of how this cross-talk occurs in the skin, gut, and lungs. An improved understanding of the communication between the immune and nervous system may lead to the development of novel therapies for allergic diseases.

Lactobacillus casei HY2782 and Pueraria lobata Root Extract Complex Ameliorates Particulate Matter-Induced Airway Inflammation in Mice by Inhibiting Th2 and Th17 Immune Responses.

This study aimed to investigate the effects of Lactobacillus casei HY2782 and Pueraria lobata root extract complex (HY2782 complex) in mitigating airway inflammation resulting from exposure to particulate matter ≤2.5 μm in diameter (PM2.5) in an animal model. Chronic inflammatory airway disease is associated with Th2-related cytokines interleukin (IL)-4, IL-5, and IL-13 and Th17-related cytokine IL-17A, which are the major contributors to allergy and asthma. Results indicated that PM2.5 elevates allergen-related airway inflammation and respiratory hyperresponsiveness in C57BL/6 mice. The HY2782 complex significantly reduced Th2/Th17-derived cytokines IL-4, IL5, IL-13, and IL-17A; immunoglobulin E; and leukotriene C4 in bronchoalveolar lavage fluid (BALF) and serum. Furthermore, the HY2782 complex was associated with the modulation of oxidative stress-related genes. Administration of the HY2782 complex resulted in a markedly reduced number of neutrophils and eosinophil infiltration in BALF. Histopathological observation of lung tissue also showed reduced inflammatory cell infiltration into airways and surrounding tissue. The HY2782 complex may be a promising candidate for the preventive therapy of allergic diseases and airway inflammation caused by PM2.5 inhalation.

Loss of isoprenylation significantly reduces IgE mediated mast cell activation

Abstract Allergic disease is the 6th leading cause of chronic illness in the US and accounts for billions of dollars in healthcare costs annually. Mast cells are tissue resident innate immune cells linked to allergic disease and activated by IgE and other ligands. Upon activation they release histamine, cytokines, chemokines, proteases, and lipid mediators evoking allergic symptoms. New ways of targeting mast cells could greatly benefit allergic disease therapy. Previous findings showed repurposing of statin drugs, such as Fluvastatin, reduced allergic symptoms in vitro and in vivo. We found that Fluvastatin suppresses IgE-mediated mast cell activation by inhibiting isoprenylation of proteins. However, statin effects were dependent on genetic background. To avert genetic background dependency, we tested the hypothesis that a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734) would suppress allergic disease withoutgenetic background limitations. We show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production by bone marrow derived mast cells from multiple genetic backgrounds. Similarly, FGTI 2734 also suppressed IgE-mediated anaphylaxis on multiple genetic backgrounds. These in vivo effects extended to an allergic asthma model, in which FGTI 2734 inhibited pulmonary inflammation. Finally, we show that FGTI-2734 can significantly reduce IgE-induced cytokine production from human skin mast cells. These data show that dual farnesyl and geranylgeranyl transferase inhibitors may be an effective therapeutic treatment for mast cell-associated diseases. Supported by NIH (1RO1AI101153)

Combining Biologic Therapies Involving Anti-IgE, Anti-IL5, Anti-IL5R and Anti IL-4/IL-13: Experience from a Large Academic Health System

The indications for biologic therapy in allergic diseases are expanding. Patients may benefit from different biologics for separate conditions or one condition with multiple pathogenic mechanisms that may be targeted by different biologics. There is a paucity of data regarding the safety and efficacy of combining biologic therapies.

Immunology of allergen immunotherapy.

Allergen immunotherapy (AIT) is the only disease-modifying therapy for allergic disease. Through repeated inoculations of low doses of allergen-either as whole proteins or peptides-patients can achieve a homeostatic balance between inflammatory effectors induced and/or associated with allergen contact, and mediators of immunologic non-responsiveness, potentially leading to sustained clinical improvements. AIT for airborne/respiratory tract allergens and insect venoms have traditionally been supplied subcutaneously, but other routes and modalities of administration can also be effective. Despite differences of allergen administration, there are some similarities of immunologic responses across platforms, with a general theme involving the restructuring and polarization of adaptive and innate immune effector cells. Here we review the immunology of AIT across various delivery platforms, including subcutaneous, sublingual, epicutaneous, intradermal, and intralymphatic approaches, emphasizing shared mechanisms associated with achieving immunologic non-responsiveness to allergen.

Current State of Monoclonal Antibody Therapy for Allergic Diseases

Allergic disease is one of the most common chronic diseases, which can affect both children and adults, be often caused by allergen-induced unfavorable immune responses, and initiate various symptoms in different organs, including up-/low-airways and skin, such as asthma, atopic dermatitis, and rhinosinusitis. With increasing prevalence of allergic disease worldwide and their impact on the quality of life, new biological therapeutic approaches for these disorders become hot areas of intensive research. Multiple factors are involved and play important role in the pathogenesis of allergic disease, which can promote or trigger T helper 2 (Th2)-type immune responses, leading to production of the type 2 cytokines and immunoglobulin E (IgE)，the two critical events in the allergic diseases. Using monoclonal antibodies to target these molecules, therefore, might provide possible benefits for the patients suffered from these diseases. Apart of those having approved biologics for allergic diseases, some potential targets such as epithelial-derived alarmins thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33) have been also described and proposed to develop monoclonal antibodies against either these cytokines, their receptors, or both. These new and potential targets have substantially enriched the therapeutic opportunities in the field of allergic diseases. The present review aims to briefly outline the role of monoclonal antibodies targeting the cytokines and immunoglobulin involved in the development of allergic diseases, and to discuss the clinical effects of these antibodies.

Design aspects of the combined medicinal product with multifunctional action based on herbal drugs

Combined herbal medicines for the treatment and prevention of allergic diseases are perspective substitutes for the «classic» drugs of H-1 receptor blockers of the 1st and 2nd generation. Literary-logical methods are quite effectively used for scientifically justified design of these drugs, namely phytopharmacological drug design (PPD) and phytochemical drug design (PCD).
 The aim of the work – the search for ways of the scientifically justified design of a combined multifunctional medicine based on the bur-marigold, which normalizes the functioning of the body's defence systems, increases the body's nonspecific resistance, normalizes the immune status using literary-logical and statistical methods of analysis.
 The design of the preparation was carried out using literature data for PPD and experimental and literature data for PCD. Statistical processing method – Spearman's rank correlation coefficient was used.
 Design aspects of the combined herbal medicine, which includes a bur-marigold herb, calendula flowers, hawthorn leaves and flowers were considered using of a system-comparative analysis of information and its processing by the method of the Spearman's rank correlation coefficient determination. When PCD development of various combinations of herbal drugs, information about the content of such biologically active substances (BAS) as flavonoids, oxycinnamic acids, polyphenols, triterpenes, proteins/amino acids, polysaccharides was used. When PPD development the spectra of pharmacological activity were determined and a quantitative assessment to them in the system of marks for each of the herbal drug of the combined medicine was given. The PCD and PPD data into the matrix for calculating the Spearman rank correlation coefficient of the «action–sum of BAS» was entered. As a result, a strong, direct and statistically significant correlation relation (p from 0.924 to 0.997) between the content of oxycinnamic acids, polyphenols, triterpenes, proteins/amino acids, polysaccharides and such pharmacological actions as capillary-strengthening, anti-inflammatory, immunostimulating; choleretic, hepatoprotective, improving metabolism; diuretic, hypotensive, sedative, tonic, desensitizing, antipruritic, reparative for the studied herbal combinations was found.
 The obtained results of the PCD and PPD development as well as the study of the correlation «action–sum of BAS» by calculating the Spearman's rank correlation coefficient, this suggests the developed combined herbal medicinal product with multifunctional action is perspective in the complex therapy of allergic diseases accompanied by a decrease in the body's resistance and immunostatus.

Allergic Inflammation Caused by Dimerized Translationally Controlled Tumor Protein is Attenuated by Cardamonin

We demonstrated in our previous reports that dimeric form of translationally controlled tumor protein (dTCTP) initiates a variety of allergic phenomena. In the present study, we examined whether and how dTCTP’s role in allergic inflammation can be modulated or negated. The possible potential of cardamonin as an anti-allergic agent was assessed by ELISA using BEAS-2B cells and OVA-challenged allergic mouse model. The interaction between cardamonin and dTCTP was confirmed by SPR assay. Cardamonin was found to reduce the secretion of IL-8 caused by dTCTP in BEAS-2B cells by interacting with dTCTP. This interaction between dTCTP and cardamonin was confirmed through kinetic analysis (KD = 4.72 ± 0.07 μM). Also, cardamonin reduced the migration of various inflammatory cells in the bronchoalveolar lavage fluid (BALF), inhibited OVA specific IgE secretion and bronchial remodeling. In addition, cardamonin was observed to have an anti-allergic response by inhibiting the activity of NF-κB. Cardamonin exerts anti-allergic anti-inflammatory effect by inhibiting dTCTP, suggesting that it may be useful in the therapy of allergic diseases.

One hundred and ten years of Allergen Immunotherapy: A journey from empiric observation to evidence.

One hundred and ten years after Noon's first clinical report of the subcutaneous application of allergen extracts, allergen immunotherapy (AIT) has evolved as the most important pillar of the treatment of allergic patients. It is the only disease-modifying treatment option available and the evidence for its clinical efficacy and safety is broad and undisputed. Throughout recent decades, more insights into the underlying mechanisms, in particular the modulation of innate and adaptive immune responses, have been described. AIT is acknowledged by worldwide regulatory authorities, and following the regulatory guidelines for product development, AIT products are subject to a rigorous evaluation before obtaining market authorization. Knowledge and practice are anchored in international guidelines, such as the recently published series of the European Academy of Allergy and Clinical Immunology (EAACI). Innovative approaches continue to be further developed with the focus on clinical improvement by, for example, the usage of adjuvants, peptides, recombinants, modification of allergens, new routes of administration, and the concomitant use of biologicals. In addition, real-life data provide complementary and valuable information on the effectiveness and tolerability of this treatment option in the clinical routine. New mobile health technologies and big-data approaches will improve daily treatment convenience, adherence, and efficacy of AIT. However, the current coronavirusdisease2019(COVID-19) pandemic has also had some implications for the feasibility and practicability of AIT. Taken together, AIT as the only disease-modifying therapy in allergic diseases has been broadly investigated over the past 110years laying the path for innovations and further improvement.

Research on allergen detection technology and allergic disease diagnosis strategy in China

In China, the prevalence of allergic diseases is increasing, but allergy research and allergy diagnosis technologies are still in their infancy, posing certain hurdles to clinical diagnosis and treatment. The detection of allergen is essential for the prevention and treatment of allergic diseases. Clarifying the aetiology and risk factors of allergic diseases is critical in order to provide targeted environmental control and therapy for allergic diseases, as well as reduce patient pain and financial burden. In this study, allergen detection technologies and diagnosis strategies are described in order to provide direction for clinicians and laboratory technicians, improve allergic diseases diagnosis, and guide allergic disease therapy.

Adenosine Signaling in Mast Cells and Allergic Diseases.

Adenosine is a nucleoside involved in the pathogenesis of allergic diseases. Its effects are mediated through its binding to G protein-coupled receptors: A1, A2a, A2b and A3. The receptors differ in the type of G protein they recruit, in the effect on adenylyl cyclase (AC) activity and the downstream signaling pathway triggered. Adenosine can produce both an enhancement and an inhibition of mast cell degranulation, indicating that adenosine effects on these receptors is controversial and remains to be clarified. Depending on the study model, A1, A2b, and A3 receptors have shown anti- or pro-inflammatory activity. However, most studies reported an anti-inflammatory activity of A2a receptor. The precise knowledge of the adenosine mechanism of action may allow to develop more efficient therapies for allergic diseases by using selective agonist and antagonist against specific receptor subtypes.

Loss of isoprenylation significantly reduces IgE mediated mast cell activation

Abstract Allergic disease a leading cause of chronic illness in the US and accounts for billions of dollars in healthcare costs annually. Mast cells are tissue resident innate immune cells linked to allergic disease and activated by IgE and other ligands. Upon activation they release histamine, cytokines, chemokines, proteases, and lipid mediators evoking allergic symptoms. New ways of targeting mast cells could greatly benefit allergic disease therapy. Repurposing statin drugs such as Fluvastatin as a therapeutic treatment of allergic disease showed reduced allergic symptoms using in vitro and in vivo mouse models. We found the Fluvastatin suppresses IgE mediated mast cell activation by inhibiting protein isoprenylation. However, statin suppression is dependent on genetic background. To avert genetic background dependency, we tested the hypothesis that a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734) would consistently suppress mast cell function. We show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production similar to Fluvastatin effects, but maintained efficacy on fluvastatin-resistant genetic backgrounds. FGTI 2734 also suppressed IgE-mediated anaphylaxis in vivo on multiple genetic backgrounds. Finally, inhibition of Ras, a known target of prenylation, can mimic statin effects on IgE-mediated mast cell function. These data support the hypothesis that dual farnesyl and geranylgeranyl transferase inhibitors may be an effective therapeutic treatment for mast cell-associated diseases.