Novel Immunopharmacological Drugs for the Treatment of Allergic Diseases.

The exponential rise in the prevalence of allergic diseases since the mid-twentieth century has led to a genuine public health emergency and has also fostered major progress in research on the underlying mechanisms and potential treatments. The management of allergic diseases benefits from the biological revolution, with an array of novel immunomodulatory therapeutic and investigational tools targeting players of allergic inflammation at distinct pathophysiological steps. Prominent examples include therapeutic monoclonal antibodies against cytokines, alarmins, and their receptors, as well as small-molecule modifiers of signal transduction mainly mediated by Janus kinases and Bruton's tyrosine kinases. However, the first-line therapeutic options have yet to switch from symptomatic to disease-modifying interventions. Here we present an overview of available drugs in the context of our current understanding of allergy pathophysiology, identify potential therapeutic targets, and conclude by providing a selection of candidate immunopharmacological molecules under investigation for potential future use in allergic diseases.

Mast cells contribute to the resolution of allergic inflammation by releasing resolvin D1.

BACKGROUND: Mast cells are initiators and main effectors of allergic inflammation, together with eosinophils, with whom they can interact in a physical and soluble cross-talk with marked pro-inflammatory features, the Allergic Effector Unit. The pro-resolution role of mast cells, alone or in co-culture with eosinophils, has not been characterized yet. OBJECTIVES: We aimed to investigate select pro-resolution pathways in mast cells in vitro and in vivo in allergic inflammation. METHODS: In vitro, we employed human and murine mast cells and analyzed release of resolvin D1 and expression of 15-lipoxygenase after IgE-mediated activation. We performed co-culture of IgE-activated mast cells with peripheral blood eosinophils and investigated 15-lipoxygenase expression and Resolvin D1 release. In vivo, we performed Ovalbumin/Alum and Ovalbumin/S. aureus enterotoxin B allergic peritonitis model in Wild Type mice following a MC "overshoot" protocol. RESULTS: We found that IgE-activated mast cells release significant amounts of resolvin D1 30 min after activation, while 15-lipoxygenase expression remained unchanged. Resolvin D1 release was found to be decreased in IgE-activated mast cells co-cultured with peripheral blood eosinophils for 30 min In vivo, mast cell-overshoot mice exhibited a trend of reduced inflammation, together with increased peritoneal resolvin D1 release. CONCLUSIONS: Mast cells can actively contribute to resolution of allergic inflammation by releasing resolvin D1.

Patients with coronavirus disease 2019 characterized by dysregulated levels of membrane and soluble cluster of differentiation 48.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can progress into a severe form of acute lung injury. The cosignaling receptor cluster of differentiation 48 (CD48) exists in membrane-bound (mCD48) and soluble (sCD48) forms and has been reported to be implicated in antiviral immunity and dysregulated in several inflammatory conditions. Therefore, CD48 dysregulation may be a putative feature in COVID-19-associated inflammation that deserves consideration. OBJECTIVE: To analyze CD48 expression in lung autopsies and peripheral blood leukocytes and sera of patients with COVID-19. The expression of the CD48 ligand 2B4 on the membrane of peripheral blood leukocytes was also assessed. METHODS: Twenty-eight lung tissue samples obtained from COVID-19 autopsies were assessed for CD48 expression using gene expression profiling immunohistochemistry (HTG autoimmune panel). Peripheral whole blood was collected from 111 patients with COVID-19, and the expression of mCD48 and of membrane-bound 2B4 was analyzed by flow cytometry. Serum levels of sCD48 were assessed by enzyme-linked immunosorbent assay. RESULTS: Lung tissue of patients with COVID-19 showed increased CD48 messenger RNA expression and infiltration of CD48+ lymphocytes. In the peripheral blood, mCD48 was considerably increased on all evaluated cell types. In addition, sCD48 levels were significantly higher in patients with COVID-19, independently of disease severity. CONCLUSION: Considering the changes of mCD48 and sCD48, a role for CD48 in COVID-19 can be assumed and needs to be further investigated.

Histamine research advancements in the second year of the COVID-19 pandemic: report of the European Histamine Research Society (EHRS).

In the light of cancellation of the 50th Annual Meeting of the European Histamine Research Society (EHRS) due to continuing challenges and restrictions imposed by the coronavirus disease 2019 (COVID-19) outbreak, the EHRS Council decided to organize a series of online events spread in 2021 to allow dissemination of histamine research progress and advancement among the Society members and beyond. This report summarizes the outcomes of the EHRS Council initiative that comprised the organization of four webinars, each focusing on a highly relevant histamine research scientific area. These included insights into novel therapeutic targets related to the histaminergic system in the eye, histamine intolerance, and the role of histamine and the histaminergic system in the regulation of the nervous system, as well as an update on studies leading to the development of novel methods for histamine detection. The outcome of this series of virtual events conformed that histamine research continued to develop despite the pandemic, and we witnessed stimulating advancements in 2021. Importantly, the EHRS Council brought histaminologists together in this unprecedented time.

"Novel insights into the roles of mast cells and basophils": Joint Webinar of the Japanese and the European Histamine Research Societies (JHRS/EHRS).

The joint webinar of the Japanese (JHRS) and the European (EHRS) Histamine Research Society focusing on "Novel insights into the roles of mast cells and basophils" was organized in hybrid format on January 7, 2022 during the 23rd meeting of the JHRS held in Kyoto, Japan. Tissue mast cells and circulating basophils are the primary sources of histamine, and they are considered to be pivotal components shaping inflammatory and immune-related processes. The webinar comprised four lectures delivered by experts in the field from Japan and the European Mast Cell and Basophil Research Network (EMBRN) that exposed novel insights into the contribution of basophils and mast cells in inflammatory and (auto)immune diseases, including allergies, asthma, and urticaria. Several targets were also highlighted in terms of developing novel and improved treatments for these pathologies.

Granulocyte-targeted therapies for airway diseases.

The average respiration rate for an adult is 12-20 breaths per minute, which constantly exposes the lungs to allergens and harmful particles. As a result, respiratory diseases, which includes asthma, chronic obstructive pulmonary disease (COPD) and acute lower respiratory tract infections (LTRI), are a major cause of death worldwide. Although asthma, COPD and LTRI are distinctly different diseases with separate mechanisms of disease progression, they do share a common feature - airway inflammation with intense recruitment and activation of granulocytes and mast cells. Neutrophils, eosinophils, basophils, and mast cells are crucial players in host defense against pathogens and maintenance of lung homeostasis. Upon contact with harmful particles, part of the pulmonary defense mechanism is to recruit these cells into the airways. Despite their protective nature, overactivation or accumulation of granulocytes and mast cells in the lungs results in unwanted chronic airway inflammation and damage. As such, understanding the bright and the dark side of these leukocytes in lung physiology paves the way for the development of therapies targeting this important mechanism of disease. Here we discuss the role of granulocytes in respiratory diseases and summarize therapeutic strategies focused on granulocyte recruitment and activation in the lungs.

Challenges in the development and exploitation of new therapeutic options targeting the histaminergic system.

LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century Antihistamines. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Histamine pharmacology: from Sir Henry Dale to the 21st century.

Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho)physiological processes. It elicits its multifaceted modulatory functions by activating four types of GPCRs, designated as H1-4 . Despite the heterogeneity and the complexity of histamine receptor pharmacology, many discoveries over the past 100 years resulted in the development of H1 antihistamines and H2 -targeting 'blockbuster' therapeutics for the management of allergies and gastrointestinal disorders respectively. Recently, a first-in-class H3 inverse agonist was approved for the treatment of narcolepsy, whereas H4 antagonists are under clinical evaluation for their potential therapeutic exploitation in immune-related diseases. This review critically presents the past successes and drawbacks in histamine research, complemented by the modern conceptual innovations in molecular and receptor pharmacology. It targets both young and experienced researchers in an ongoing effort to stimulate novel insights for the dissection of the translational potential of histamine pharmacology. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Increased Basal Blood Histamine Levels in Patients with Self-Reported Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most prevalent causes of drug hypersensitivity reactions (DHRs), yet the underlying processes are far from clear. Despite the established role of histamine in allergic reactions, its precise implication in DHRs is elusive. OBJECTIVES: This study aimed to explore the connection of basal blood histamine levels to the reported NSAID hypersensitivity. METHODS: Sixteen patients reporting hypersensitivity reactions to a single or multiple NSAIDs and/or paracetamol and 18 healthy volunteers serving as the normal control group enrolled in the study. The medical history was recorded and histamine was quantified spectrophotofluorometrically in whole peripheral blood and plasma. RESULTS: Compared to the normal group, plasma but not whole blood histamine levels were significantly higher in patients (p < 0.001), mainly in the subgroup reporting hypersensitivity to a single agent (p < 0.001). Plasma histamine levels were significantly correlated with the culprit drug selectivity for cyclooxygenase (COX) isozymes (p < 0.001), with higher levels being obtained in patients reporting reactions to COX-1 than to COX-2 selective inhibitors (p < 0.05). CONCLUSIONS: The findings provide first evidence connecting basal blood histamine levels to the reported NSAID-triggered DHRs. Prospective studies are expected to decipher the contribution of histamine-associated parameters to the mechanisms underlying DHRs.

L-Thyroxine induces thermotolerance in yeast.

The cellular stress response (CSR) is a universal inducible reaction modulated, among others, by heat, drugs, and hormones. We aimed to investigate the role of L-thyroxine (T4) on the heat shock (HS) response in Saccharomyces cerevisiae. The CSR was evaluated by determining growth and viability of post-logarithmic phase grown yeast cultures after HS at 53 °C for 30 min. We found that long-term T4 exposure can induce a dose-dependent and Hsp90 and H+ trafficking-related thermotolerance in yeast.

Detection of local allergic rhinitis in children with chronic, difficult-to-treat, non-allergic rhinitis using multiple nasal provocation tests.

BACKGROUND: There is little evidence on the incidence and characteristics of local allergic rhinitis (LAR) in children. Most studies have included subjects with perennial rhinitis only, and results are based on the investigation of no more than three allergens per study. Our aim was to determine the proportion of children with LAR amongst children with chronic, difficult-to-treat, perennial or seasonal, rhinitis but no evidence of sensitization to aeroallergens, or other alternative diagnosis. METHODS: We performed multiple nasal provocation tests (M-NPTs) with four locally relevant aeroallergens (Phleum pratense, Olea europea, Alternaria alternata, and Dermatophagoides pteronyssinus) in children with absence of aeroallergen sensitization, seen during a calendar year in a specialized rhinitis clinic. We additionally performed single NPT to children with allergic rhinitis (AR; positive control group). The result of the NPT was based on symptoms and acoustic rhinometry. Identification of nasal hyper-reactivity (NHR) triggers was through a questionnaire. RESULTS: Local allergic rhinitis was confirmed in 29.2% (7/24) of the negative SPT/blood testing population. All but one of the children reacted to one allergen and one to two. All AR children had positive single NPT with results similar to the LAR. There were no differences in age at examination and rhinitis onset, gender distribution, family atopy, and past or current environment of residency, while the prevalence of reported NHR triggers was comparable amongst the three groups. CONCLUSION: This is the first pediatric study where the seasonal or perennial rhinitis population was thoroughly tested for LAR against four aeroallergens. LAR is present in a considerable proportion of children with chronic, difficult-to-treat rhinitis and no sensitization to aeroallergens, and therefore, the performance of NPT should be strongly considered in these cases. There were no distinct clinical characteristics between LAR, AR, and non-allergic rhinitis in children.

Dimethyl sulphoxide modifies growth and senescence and induces the non-revertible petite phenotype in yeast.

Dimethyl sulphoxide is extensively used in chemical, pharmaceutical and biomedical applications, but its specific biological actions remain largely elusive. The aim of this study was to comprehensively explore the effects of dimethyl sulphoxide on eukaryotic growth and senescence by using the budding yeast Saccharomyces cerevisiae as a reliable model organism. Rather than focusing on single cells or on either the replicative or the chronological lifespan approach, well-established microbiological procedures were integrated to monitor a combination of physiological parameters. Cell proliferation, survival, reproductive competence and morphology were recorded at various time points during incubation of asynchronous yeast populations with increasing concentrations of dimethyl sulphoxide. The findings demonstrated a dose-dependent inhibitory effect of the compound on yeast proliferation, survival and reproduction. In parallel, dimethyl sulphoxide induced the acquisition of the non-revertible petite phenotype and promoted morphological alterations that characterize senescence, driving the yeast populations towards the reproductive incompetent state. These findings point to the need for the investigation of the complex cellular and/or molecular mechanisms underlying the actions of dimethyl sulphoxide in eukaryotic cells and for the evaluation of their exploitation potential.

The expanding role of immunopharmacology: IUPHAR Review 16.

Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacological research have made available new classes of clinically relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies, that selectively modulate the immune response not only in cancer and autoimmunity but also in a number of other human pathologies. Likewise, more effective vaccines utilizing novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen-specific immunotherapy. Consequently, immunopharmacology is presently considered as one of the expanding fields of pharmacology. Immunopharmacology addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non-typical immune system-driven unmet clinical needs. While in the near future a number of new agents will be introduced, improving the effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunology, pharmacology and drug discovery. The newly formed ImmuPhar (http://iuphar.us/index.php/sections-subcoms/immunopharmacology) is the Immunopharmacology Section of the International Union of Basic and Clinical Pharmacology (IUPHAR, http://iuphar.us/). ImmuPhar provides a unique international expert-lead platform that aims to dissect and promote the growing understanding of immune (patho)physiology. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases.

Histamine H3 and H4 receptor ligands modify vascular histamine levels in normal and arthritic large blood vessels in vivo.

Growing evidence associates histamine with arthritis, but its implication in shaping vascular function in chronic inflammation remains largely elusive. This study explored the involvement of vascular histamine in the extra-articular responses in peripheral large blood vessels using a rat model of adjuvant-induced arthritis. Histamine levels were increased in the abdominal aorta and the inferior vena cava of arthritic animals. Contrary to the H1 receptor antagonist dimetindene, histamine induction was observed following administration of the H3 and H4 receptor ligands GSK334429 and JNJ7777120, respectively. In arthritis, prophylactic treatment with GSK334429 partially attenuated the clinical signs and restored basal histamine levels only in the abdominal aorta. This study is the first to implicate the H3 and H4 receptors in a concerted constitutive regulation of basal vascular histamine in the rat large blood vessels and to identify the H3 receptor as a component that may influence arterial histamine during the onset of arthritis.

Seasonal influence on mitogen and cyclosporin responses of peripheral blood lymphocytes.

The immune response and lymphocyte activation in particular are affected by environmental factors. In vivo and in vitro experiments demonstrate variability in lymphocyte activation according to seasonal changes. This study focused on the effects of season on the ex vivo mitogen-induced activation of lymphocytes from peripheral blood of healthy humans living in a temperate climate, as well as the ex vivo lymphocyte activation of rabbits living under constant laboratory conditions. The possible impact of season on the action of the immunosuppressant drug cyclosporin A (CsA) on lymphocyte activation was investigated in both species. Cultured peripheral blood lymphocytes from human donors (n=13, 22-63years of age) and from animals housed under 12:12hour light:dark cycle were stimulated with phytohemagglutinin (PHA) in the absence or presence of 10 and 25µg/mL CsA. Lymphocyte activation was assessed by morphometric analysis under a light microscope. Percentages of unactivated lymphocytes, activated lymphoblasts and aberrant cells reflecting cytotoxicity were determined. Human lymphocytes demonstrated a significant decrease in response to PHA during the winter months, in comparison to the rest of the year. In contrast, the peripheral blood lymphocytes of rabbits housed under constant conditions did not demonstrate similar variations in response to PHA stimulation. The immunosuppressive action of cyclosporin A on this experimental model was unaffected by the observed seasonal variation in mitogen response in humans. These findings may guide research towards the identification of factors associated with the seasonality of the immune response and its potential influence on therapeutic interventions.

Histamine involvement in visual development and adaptation.

PURPOSE: This study evaluated the level of histamine in the interaction between the environment and the visual system during lifespan development, exploring potential sex differences. METHODS: Male and female Wistar rats, reared in standard laboratory or enriched-environment cages from birth to prepuberty or adulthood, were sacrificed during the critical period for visual development at postnatal day (P) 25 (P25) or in adulthood at P90. Additionally, animals born in standard conditions were exposed to an enriched environment at P90 and sacrificed at P150. The optic chiasm and the visual cortex were dissected out and tissue histamine was quantified fluorophotometrically. Statistical analyses were performed by ANOVA. RESULTS: Histamine levels in the optic chiasm were higher in male than in female rats at all ages. Comparable sex differences in the visual cortex were observed only during prepuberty. Basal histamine content in the optic chiasm was higher in prepuberty and decreased in adulthood in a sex-independent manner. Exposure to an enriched environment decreased optic chiasm histamine levels in both sexes and resulted in no sex difference in the cortical histamine levels at any age. Increased amine levels were detected in the optic chiasm of female rats exposed to an enriched environment during adulthood. CONCLUSIONS: This study presents first evidence associating central histamine levels with the visual system development and environmental adaptation, thus providing the lead for the investigation of the hitherto elusive role of histamine in the regulation of visual processes. Furthermore, the findings challenge the impact of laboratory animal raising environments in developmental and behavioral studies.

Histamine in two component system-mediated bacterial signaling.

Histamine is a key mediator governing vital cellular processes in mammals beyond its decisive role in inflammation. Recent evidence implies additional actions in both eukaryotes and prokaryotes. Besides its function in host defense against bacterial infections, histamine elicits largely undefined actions in microorganisms that may contribute to bacteria-host interactions. Bacterial proliferation and adaptation are governed by sophisticated signal transduction networks, including the versatile two-component systems (TCSs) that comprise sensor histidine kinases and response regulators and rely on phosphotransfer mechanisms to exert their modulatory function. The AtoSC TCS regulates fundamental cellular processes such as short-chain fatty acid metabolism, poly-(R)-3-hydroxybutyrate (cPHB) biosynthesis and chemotaxis in Escherichia coli. The implication of exogenous histamine in the AtoSC-mediated cPHB biosynthesis and in E. coli chemotactic behavior is indicative of a putative function of histamine in bacterial physiology. The data raise questions on the significance of histamine actions in bacteria-host symbiosis, dysbiosis and pathogenicity as well as on the possible consequences upon therapeutic administration of histamine receptor-targeting agents and in particular ligands of the recently identified immunomodulatory H4 receptor.

Histamine pharmacology and new CNS drug targets.

During the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H(3) and H(4) receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H(3) receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's, or Parkinson's disease, while the first H(3) receptor ligands have already entered phase I-III clinical trials. Interestingly, the localization of the immunomodulatory H(4) receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current "translational research" approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration.