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Background: Allergy represents a major health problem of increasing prevalence worldwide with a high socioeconomic impact. Our knowledge on the molecular mechanisms underlying allergic diseases and their treatments has significantly improved over the last years. The generation of allergen-specific regulatory T cells (Tregs) is crucial in the induction of healthy immune responses to allergens, preventing the development and worsening of allergic diseases. Summary: In the last decades, intensive research has focused on the study of the molecular mechanisms involved in Treg development and Treg-mediated suppression. These mechanisms are essential for the induction of sustained tolerance by allergen-specific immunotherapy (AIT) after treatment discontinuation. Compelling experimental evidence demonstrated altered suppressive capacity of Tregs in patients suffering from allergic rhinitis, allergic asthma, food allergy, or atopic dermatitis, as well as the restoration of their numbers and functionality after successful AIT. Key Message: The better understanding of the molecular mechanisms involved in Treg generation during allergen tolerance induction might well contribute to the development of novel strategies for the prevention and treatment of allergic diseases. [ABSTRACT FROM AUTHOR]

This article discusses the factors that determine the differentiation of autoreactive thymocytes into regulatory T cells (Tregs). Tregs are a subset of CD4+ T cells that play a crucial role in maintaining peripheral tolerance and immune homeostasis. The majority of Tregs are generated in the thymus upon recognition of self-antigens, while others can be generated in specialized peripheral tissues. The differentiation of Tregs is influenced by factors such as T-cell receptor signaling, co-stimulation, and the presence of TGF-β and retinoic acid. The study also highlights the role of late agonist signaling and the disruption of TCR signaling in the generation of Tregs. The findings contribute to our understanding of thymocyte selection and central tolerance, and may have implications for future therapeutic interventions involving Tregs. [Extracted from the article]

Background: Ligelizumab is an anti‐IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE‐mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN‐α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab. Methods: pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53‐79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE‐FcεRI crosslinking and Toll‐like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen‐specific model of resensitization and IgE‐crosslinking was also performed. Results: The levels of serum total free IgE show a non‐linear positive correlation with the frequency of IgE+ pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9‐L‐induced IFN‐α production. Ligelizumab also restores the ability of pDCs to generate FOXP3+ Tregs as previously reported for omalizumab. Conclusions: The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti‐IgE treatments in different IgE‐mediated diseases. [ABSTRACT FROM AUTHOR]

Keywords: allergen-specific immunotherapy; allergoid-mannan conjugates; human macrophages; immune regulation; innate immunity EN allergen-specific immunotherapy allergoid-mannan conjugates human macrophages immune regulation innate immunity 320 323 4 12/31/21 20220101 NES 220101 ACKNOWLEDGEMENT None. Allergoid-mannan conjugates imprint tolerogenic features in human macrophages LPS-stimulated Mannan-GM-MØ produced significantly lower levels of the pro-inflammatory cytokines TNF- and IL-6 and significantly higher levels of anti-inflammatory IL-10 than conventional GM-MØ (Figure 2D). [Extracted from the article]

Background: Polymerized allergoids conjugated to mannan (PM) are suitable vaccines for allergen‐specific immunotherapy (AIT). Alum remains the most widely used adjuvant in AIT, but its way of action is not completely elucidated. The better understanding of the mechanisms underlying alum adjuvanticity could help to improve AIT vaccine formulations. Objective: We sought to investigate the potential influence of alum in the tolerogenic properties imprinted by PM at the molecular level. Methods: Flow cytometry, ELISAs, cocultures, intracellular staining and suppression assays were performed to assess alum and PM effects in human dendritic cells (DCs). BALB/c mice were immunized with PM alone or adsorbed to alum. Allergen‐specific antibodies, splenocyte cytokine production and splenic forkhead box P3 (FOXP3)+ regulatory T (Treg) cells were quantified. Metabolic and immune pathways were also studied in human DCs. Results: Alum decreases PD‐L1 expression and IL‐10 production induced by PM in human DCs and increases pro‐inflammatory cytokine production. Alum impairs PM‐induced functional FOXP3+ Treg cells and promotes Th1/Th2/Th17 responses. Subcutaneous immunization of mice with PM plus alum inhibits in vivo induction of Treg cells promoted by PM without altering the capacity to induce functional allergen‐specific blocking antibodies. Alum inhibits mTOR activation and alters metabolic reprogramming by shifting glycolytic pathways and inhibiting reactive oxygen species (ROS) production in PM‐activated DCs, impairing their capacity to generate functional Treg cells. Conclusion: We uncover novel mechanisms by which alum impairs the tolerogenic properties induced by PM, which might well contribute to improve the formulation of novel vaccines for AIT. [ABSTRACT FROM AUTHOR]

Therapeutic advances using targeted biologicals and small‐molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment‐resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell–based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell–based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell–based approaches, especially Treg‐based approaches, in severe IgE‐mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment‐resistant forms of these immune‐driven disorders. [ABSTRACT FROM AUTHOR]

Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody‐based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)‐based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs‐ and antibody‐based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases. [ABSTRACT FROM AUTHOR]