Therapy Of Allergic Diseases Research Articles

Translational Allergy and Omalizumab: The Pioneer

Abstract: Backgound: The introduction of monoclonal antibodies into therapy has brought great progress in every field of medicine. Omalizumab is the first monoclonal antibody successfully used in allergology. We wanted to evaluate the impact in the medical literature of this molecule. Materials and Methods: We have identified omalizumab as the reference molecule in clinical allergology to evaluate the impact of the translational approach in this field throw the amount of data present in the literature on this subject. We have therefore carried out a research on the three main scientific databases (PubMed, Scopus and WoS) and we have documented the growing number of scientific publications on this molecule in over 20 years (1996 first publication retrived for omalizumab) and since 2003 when the molecule received the authorization by the Food and Drug Administration. Results: More than 5,000 scientific articles have been published with a maximum of almost 500 per year in 2018, which will certainly be exceeded in 2019 based on data to date. Since it is the first biologic drug approved for the treatment of immuno-allergic disorders with consolidated results in the treatment of asthma and chronic urticaria, while it is widening its therapeutic potential, we have chosen omalizumab as an example of the possibilities and successes that translational research can also reach in allergology. Conclusion: Such a significant impact of this molecule in the medical literature goes hand in hand with the leading role that this molecule has today in the therapy of allergic diseases. The impact of omalizumab in a field such as allergology in which progress is still rather slow demonstrates how, even in this discipline, understanding the finer pathogenetic mechanisms allows to develop targeted therapy with great benefits. Key words: Allergy, IgE, Atopy, Omalizumab, Asthma, Atopic dermatitis, Translational allergy, Translational medicine.

CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance.

Prevalence and incidence of IgE-mediated allergic diseases have increased over the past years in developed and developing countries. Allergen-specific immunotherapy (AIT) is currently the only curative treatment available for allergic diseases that has long-term efficacy. Although AIT has been proven successful as an immunomodulatory therapy since its beginnings, it still faces several unmet needs and challenges today. For instance, some patients can experience severe side effects, others are non-responders, and prolonged treatment schedules can lead to lack of patient adherence and therapy discontinuation. A common strategy to improve AIT relies on the use of adjuvants and immune modulators to boost its effects and improve its safety. Among the adjuvants tested for their clinical efficacy, CpG oligodeoxynucleotide (CpG-ODN) was investigated with limited success and without reaching phase III trials for clinical allergy treatment. However, recently discovered immune tolerance-promoting properties of CpG-ODN place this adjuvant again in a prominent position as an immune modulator for the treatment of allergic diseases. Indeed, it has been shown that the CpG-ODN dose and concentration are crucial in promoting immune regulation through the recruitment of pDCs. While low doses induce an inflammatory response, high doses of CpG-ODN trigger a tolerogenic response that can reverse a pre-established allergic milieu. Consistently, CpG-ODN has also been found to stimulate IL-10 producing B cells, so-called B regulatory cells (Bregs). Accordingly, CpG-ODN has shown its capacity to prevent and revert allergic reactions in several animal models showing its potential as both preventive and active treatment for IgE-mediated allergy. In this review, we describe how CpG-ODN-based therapies for allergic diseases, despite having shown limited success in the past, can still be exploited further as an adjuvant or immune modulator in the context of AIT and deserves additional attention. Here, we discuss the past and current knowledge, which highlights CpG-ODN as a potential adjuvant to be reevaluated for the enhancement of AIT when used in appropriate conditions and formulations.

Lower Functional and Proportional Characteristics of Cord Blood Treg of Male Newborns Compared with Female Newborns.

Understanding the early events involved in the induction of immune tolerance to harmless environmental antigens and microbiota compounds could reveal potential targets for allergic disease therapy or prevention. Regulatory T cells (Treg), particularly induced Treg (iTreg), are crucial for the induction and maintenance of tolerance against environmental antigens including allergens. A decrease in the number and/or function of Treg or iTreg could represent an early predictor of allergy development. We analyzed proportional and functional properties of Treg in the cord blood of children of allergic mothers (neonates at high risk of allergy development) and healthy mothers (neonates with relatively low risk of allergy development). We observed a higher number of induced Treg in the cord blood of females compared to males, suggesting an impaired capacity of male immunity to set up tolerance to allergens, which could contribute to the higher incidence of allergy observed in male infants. The decreased proportion of iTreg in cord blood compared with maternal peripheral blood documents the general immaturity of the neonatal immune system. We observed a positive correlation in the demethylation of the Treg-specific demethylated region (TSDR) and the proportion of Treg in cord blood. Our data suggest that immaturity of the neonatal immune system is more severe in males, predisposing them to increased risk of allergy development.

Biological therapy of allergic diseases during the COVID-19 pandemic

The outbreak of the SARS-CoV-2-induced Coronavirus Disease 2019 (COVID-19) pandemic started in December 2019 in Wuhan, China, continued to spread across the globe and spanned 188 countries. Under the new circumstances treatment approach for T2 allergic diseases such as asthma, chronic hives, atopic dermatitis, and sinusitis with polyps has been changed. In the past years, new biological therapies monoclonal antibodies for these diseases have been developed targeting different aspects of the type 2 immune response. New knowledge on the COVID-19 disease course raises many issues around the safety of biologicals in patients with active infection, as well as their interactions with antiviral medications. In Russia new biological therapies entered clinical practice but its effectiveness and safety still are not known.
 This newsletter is based on Considerations on Biologicals for Patients with allergic disease in times of the COVID-19 pandemic: an EAACI Statement and the latest scientific data.

An update on biological therapies for pediatric allergic diseases.

Allergic diseases represent a global health burden. Patients with allergic diseases may experience disability, reduced quality of life and productivity, emotional distress, and social restrictions, especially in the most severe cases. Current advances in unveiling the pathogenesis of allergic disorders have paved the way for the development of novel therapeutic strategies. Biological drugs have been widely studied in pediatric allergic asthma, with strong evidence of efficacy and safety. Moreover, promising results derive from studies on other conditions such as atopic dermatitis, chronic spontaneous urticaria, and food allergy. This review analyzes recent evidence on the role of biologic therapies for allergic diseases, focusing on the pediatric age.

Biologics in Children with Allergic Diseases.

The prevalence of allergic diseases has been remarkably increased in the last decades. The global health burden of these conditions is substantial, since patients may experience disability, anxiety and emotional distress, social restrictions, and reduced quality of life and productivity, in particular, in the most severe cases. Recent advances in understanding the pathophysiology of allergic disorders have allowed identifying novel therapeutic strategies for the treatment of severe and uncontrolled allergic diseases. Although most studies have been performed in allergic asthma, biological drugs targeting other allergic diseases such as chronic spontaneous urticaria, atopic dermatitis, and food allergy are showing promising results. In this review, the most recent evidence on biologic therapies for allergic diseases, focusing on the pediatric age has been presented.

Mechanisms of Particles in Sensitization, Effector Function and Therapy of Allergic Disease.

Humans have always been in contact with natural airborne particles from many sources including biologic particulate matter (PM) which can exhibit allergenic properties. With industrialization, anthropogenic and combustion-derived particles have become a major fraction. Currently, an ever-growing number of diverse and innovative materials containing engineered nanoparticles (NPs) are being developed with great expectations in technology and medicine. Nanomaterials have entered everyday products including cosmetics, textiles, electronics, sports equipment, as well as food, and food packaging. As part of natural evolution humans have adapted to the exposure to particulate matter, aiming to protect the individual's integrity and health. At the respiratory barrier, complications can arise, when allergic sensitization and pulmonary diseases occur in response to particle exposure. Particulate matter in the form of plant pollen, dust mites feces, animal dander, but also aerosols arising from industrial processes in occupational settings including diverse mixtures thereof can exert such effects. This review article gives an overview of the allergic immune response and addresses specifically the mechanisms of particulates in the context of allergic sensitization, effector function and therapy. In regard of the first theme (i), an overview on exposure to particulates and the functionalities of the relevant immune cells involved in allergic sensitization as well as their interactions in innate and adaptive responses are described. As relevant for human disease, we aim to outline (ii) the potential effector mechanisms that lead to the aggravation of an ongoing immune deviation (such as asthma, chronic obstructive pulmonary disease, etc.) by inhaled particulates, including NPs. Even though adverse effects can be exerted by (nano)particles, leading to allergic sensitization, and the exacerbation of allergic symptoms, promising potential has been shown for their use in (iii) therapeutic approaches of allergic disease, for example as adjuvants. Hence, allergen-specific immunotherapy (AIT) is introduced and the role of adjuvants such as alum as well as the current understanding of their mechanisms of action is reviewed. Finally, future prospects of nanomedicines in allergy treatment are described, which involve modern platform technologies combining immunomodulatory effects at several (immuno-)functional levels.

IMPROVING METHODS OF TREATMENT OF ATOPIC PATHOLOGY IN CHILDREN

The main goal of therapy for allergic diseases is to control the symptoms of the disease, prevent relapses and reduce the risk of adverse consequences of the disease. Leukotriene receptor antagonists are an effective anti-inflammatory drug for the prevention of relapses of bronchial asthma, allergic rhinitis and atopic dermatitis in children. Long-term use of montelukast (3 months) does not increase the side effects of the drug. Based on their own experience of using montelukast drugs in children from the age of two, the use of these drugs in the treatment of allergic diseases in children significantly increased the level of control of these diseases at an early age.

Defining mechanisms of semaphorin 4A stimulatory action on human Treg cells

Abstract We had shown previously that semaphorin 4A (Sema4A) suppresses allergic inflammation in mice (Mucosal Immunol., 2012, 5:409-19), regulates human Treg cell stability, and induces the generation of Treg cells in PBMC cultures acting through its Plexin B1 receptor (Immunohorizons, 2019, 3:78–87). Plexin B1 forms functional homodimers or heterodimers with other Plexin B molecules and co-precipitates with Neuropilins (NRPs) in transfected 293T cells. Furthermore, NRPs were shown to stabilize Sema/Plexin interactions. In this study, we sought to identify potential partner(s) for Plexin B1 in mediating Sema4A action. We examined surface expression of Plexin B2, B3, and NRPs 1, 2 in human Treg cells by flow cytometry, and observed that they express NRP-2 but not NRP-1, Plexin B2, or B3. Moreover, culture of PBMC with recombinant human Sema4A-Fc (rhSema4A) in vitro resulted in the downregulation of NRP-2 expression on human Treg cells suggesting a specific ligand-receptor interaction. We propose that Sema4A action on human Treg cells may be mediated by a Plexin B1-NRP-2 complex. Our ongoing research is focused on cryoEM studies of ligand-receptor and receptor-receptor interactions in conjunction with sequence/structure statistical analyses using the DARC (Deep Analysis of Residue Constraints) program (Scientific Reports, in press) with the goal of developing Sema4A-based therapies for allergic disease.

Biologics in Children with Allergic Diseases

The prevalence of allergic diseases has been remarkably increased in the last decades. The global health burden of these conditions is substantial, since patients may experience disability, anxiety and emotional distress, social restrictions, and reduced quality of life and productivity, in particular, in the most severe cases. Recent advances in understanding the pathophysiology of allergic disorders have allowed identifying novel therapeutic strategies for the treatment of severe and uncontrolled allergic diseases. Although most studies have been performed in allergic asthma, biological drugs targeting other allergic diseases such as chronic spontaneous urticaria, atopic dermatitis, and food allergy are showing promising results. In this review, the most recent evidence on biologic therapies for allergic diseases, focusing on the pediatric age has been presented.

IgE-induced mast cell function is suppressed by antagonizing isoprenylation or Ras activation

Abstract Mast cells are tissue resident innate immune cells 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. We previously found that statin drugs reduced IgE-mediated inflammation in vitro and in vivo by inhibiting production of the isoprenoid lipid geranylgeranyl pyrophosphate. However, this suppression was dependent on genetic background. To overcome this limitation, we tested a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734). Using mouse mast cells, we show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production similar to statin effects. Unlike statins, FGTI 2734 did not show a significant difference in IC50 based on genetic background. Furthermore, FGTI 2734 suppressed IgE-mediated systemic anaphylaxis in vivo. Ras GTPases are important for mast cell function and among the signaling proteins modified by isoprenylation. We show that Pan-Ras inhibitors can mimic statin and FGTI 2734 effects on cytokine production in mouse mast cells. These data indicate that dual farnesyl and geranylgeranyl transferase inhibition may be effective in suppressing IgE-induced inflammation, possibly due by disrupting Ras-mediated signals.

Аспекты физического развития детей с аллергией

The article presents an analytical review of scientific research regarding physical development of children with various allergic diseases. The specificities of physical development of children with atopy can be noted during intrauterine development, in the neonatal period and infancy. Adequate basic therapy of allergic diseases makes it possible to reduce the risk of abnormalities of physical development and manage them in preschool children and adolescents. Key words: allergic diseases, children, physical development

Clinical outcomes related to molecular allergy diagnosis.

Aim of this review is the description of the medical conditions in which the support of molecular allergy diagnostics (MAD) has an impact on the clinical outcomes, such as laboratory diagnostics, prognosis, and therapy of allergic diseases. The review of the literature of the last 2 years generated a wide number of results on this topic. As expected, not all were obtained by the use of MAD, but, in general, a clear trend is evident. Within the large number of works available, laboratory allergy diagnostics seems to be the most frequently discussed topic, in particular considering the complexity of the biological environment where these assays are used. Some interesting news arrive from the prognostic potential of MAD, whereas for allergen immunotherapy, waiting for a well-conducted prospective randomized clinical study, data from retrospective studies still confirms the added values of MAD in the management of the allergic patients.

ЭСПА-БАСТИН®: секрет успешной и безопасной терапии аллергических заболеваний

ЭСПА-БАСТИН®: секрет успешной и безопасной терапии аллергических заболеваний

Selective Serotonin Reuptake Inhibitors Suppress Mast Cell Function

Abstract Mast cells are tissue resident innate immune cells activated by IgE and many other ligands, including purines. 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. One plausible target is activation by purinergic receptors binding ligands such as ATP. However, there are currently no clinically available therapies targeting purinergic signaling. Because anti-depressants in the SSRI family can have off-target effects on purinergic receptors, we tested the hypothesis that SSRIs can attenuate mast cell function. We found that the SSRI fluoxetine blocks IgE- and ATP-induced cytokine production, degranulation, and calcium influx in murine bone marrow derived mast cells (BMMC). Furthermore, fluoxetine suppresses IgE-mediated anaphylaxis in vivo, and reduces ATP cellular uptake. Because adding serotonin to BMMC or deleting the serotonin transporter has no effect on fluoxetine-mediated suppression, an off-target effect seemed likely. We show that inhibitors of the ATP receptor P2X3 attenuate IgE-mediated activation similarly to fluoxetine, and combining fluoxetine with these inhibitors does not result in additive effects. Using siRNAs to knock down P2X3, we find that P2X3 is needed for suppression by fluoxetine. These data support the possibility of targeting purinergic signaling to treat allergic diseases, and suggest that this may be possible by repurposing FDA-approved SSRIs.

IL33: Roles in Allergic Inflammation and Therapeutic Perspectives.

Interleukin (IL)-33 belongs to IL-1 cytokine family which is constitutively produced from the structural and lining cells including fibroblasts, endothelial cells, and epithelial cells of skin, gastrointestinal tract, and lungs that are exposed to the environment. Different from most cytokines that are actively secreted from cells, nuclear cytokine IL-33 is passively released during cell necrosis or when tissues are damaged, suggesting that it may function as an alarmin that alerts the immune system after endothelial or epithelial cell damage during infection, physical stress, or trauma. IL-33 plays important roles in type-2 innate immunity via activation of allergic inflammation-related eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) through its receptor ST2. In this review, we focus on the recent advances of the underlying intercellular and intracellular mechanisms by which IL-33 can regulate the allergic inflammation in various allergic diseases including allergic asthma and atopic dermatitis. The future pharmacological strategy and application of traditional Chinese medicines targeting the IL-33/ST2 axis for anti-inflammatory therapy of allergic diseases were also discussed.

Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation.

Type 2 immunity against pathogens is tightly regulated to ensure appropriate inflammatory responses that clear infection and prevent excessive tissue damage. Recent research has shown that type 2 innate lymphoid cells (ILC2s) contribute to steady-state tissue integrity and exert tissue-specific functions. However, upon exposure to inflammatory stimuli, they also initiate and amplify type 2 inflammation by inducing mucus production, eosinophilia, and Th2 differentiation. In this review, we discuss the regulation of ILC2 activation by transcription factors and metabolic pathways, as well as by extrinsic signals such as cytokines, lipid mediators, hormones, and neuropeptides. We also review recent discoveries about ILC2 plasticity and heterogeneity in different tissues, as revealed partly through single-cell RNA sequencing of transcriptional responses to various stimuli. Understanding the tissue-specific pathways that regulate ILC2 diversity and function is a critical step in the development of potential therapies for allergic diseases.

An in Vitro and in Vivo Study of the Effect of Dexamethasone on Immunoinhibitory Function of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells

Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) represent a promising cell source for patient-specific cell therapy. We previously demonstrated that they display an immunomodulatory effect on allergic airway inflammation. Glucocorticoids are powerful anti-inflammatory compounds and widely used in the therapy of allergic diseases. However, the effect of glucocorticoids on the immunomodulatory function of iPSC-MSCs remains unknown. This study aimed to determine the effect of dexamethasone (Dex) on the immunomodulatory function of iPSC-MSCs in vitro and in vivo. A total of three human iPSC-MSC clones were generated from amniocyte-derived iPSCs. Anti-CD3/CD28-induced peripheral blood mononuclear cell (PBMC) proliferation was used to assess the effect of Dex on the immunoinhibitory function of iPSC-MSCs in vitro. Mouse models of contact hypersensitivity (CHS) and allergic airway inflammation were induced, and the levels of inflammation in mice were analyzed with the treatments of iPSC-MSCs and Dex, alone and combined. The results showed that Dex did not interfere with the immunoinhibitory effect of iPSC-MSCs on PBMC proliferation. In CHS mice, simultaneous treatment with Dex did not affect the effect of iPSC-MSCs on the inflammation, both in regional draining lymph nodes and in inflamed ear tissue. In addition, co-administration of iPSC-MSCs with Dex decreased the local expression of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in the ears of CHS mice. In the mouse model of allergic airway inflammation, iPSC-MSC treatment combined with Dex resulted in a similar extent of reduction in pulmonary inflammation as iPSC-MSCs or Dex treatment alone. In conclusion, Dex does not significantly affect the immunomodulatory function of iPSC-MSCs both in vitro and in vivo. These findings may have implications when iPSC-MSCs and glucocorticoids are co-administered.

Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today.

Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases. Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcεRI and FγR signaling, IL-4, IL-10, and TGF-β1 treatment, and Stat5. We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul. With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area.

Integrated approaches in diagnostics and therapy of allergic diseases

Allergic diseases are a serious problem in both developed and developing countries. Based on the World Health Organization data over 30-40% of the population have one or more allergic diseases. According to forecasts, by 2050, up to 4 billion people in the world will suffer from asthma, allergic rhinitis or atopic dermatitis. Solving problems related to the complexity of differential diagnosis, false positive and false negative results of clinical and laboratory studies, genetic characteristics of patients and many others, can be realized by integrating approaches of bioinformatics and systems biomedicine based on massive databases of experimental studies on one side and, on the other - on advanced technologies of genotyping and detection of biomarkers. The review analyzes the main resources of international databases on allergens, which help to determine the main characteristics of allergens: molecular weight, epitopes, cross reactivity, geographical prevalence, availability allergens in food. Different approaches are considered in the systematization of data obtained in the study of the genome, transcriptome, microbiome, comparison of data obtained from healthy donors and patients with allergic diseases, genetic mutations, transcriptome and microbiome profiles that cause severe course of allergic diseases. Several ways of depicting relationships in the construction of signaling networks (KEGG, sbvIMPROVER, Cyto scape) are shown, both on the basis of direct influence (KEGG, Cytoscape) and on the basis of OpenBEL - the open-access biological expression language - sbvIMPROVER, capable of displaying complex semantic links between components of the system under consideration.