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Keywords: cancer; hypoxia; IL-4; TGF- ; type 2 immunity EN cancer hypoxia IL-4 TGF- type 2 immunity 3563 3565 3 11/01/21 20211101 NES 211101 Abbreviations CAR chimeric antigen receptor CTL-4 cytotoxic T lymphocyte-associated protein 4 EMT epithelial-to-mesenchymal transition IL interleukin IT immunotherapy PD-1 programmed cell death protein 1 PD-L1 programmed cell death ligand 1 TGF- transforming growth factor TGFR2 TGF- receptor 2 Th T helper cell The innate and adaptive immune responses are critical for the recognition and removal of pathogens. Cancer IT, that seizes the patient's immune system to fight against cancer, has become a pivotal strategy for cancer treatment. Moreover, in the last two decades, it has been demonstrated that immune cells are also key cells in the cancer-related immune response.1 Ideally, the immune system should eradicate the tumor cells to maintain homeostasis. [Extracted from the article]

Allergen-immunotherapy (AIT) is an efficacious and disease-modifying treatment option for IgE-mediated diseases. Among these allergic rhinitis, insect venom allergy, food allergy, and allergic asthma are the most common candidates for AIT. AIT gives rise to clinical immunotolerance which may last for years after the treatment cessation. Mechanisms of AIT include suppression of allergic inflammation in target tissues and stimulation of the production of blocking antibodies, especially IgG4 and IgA. These mechanisms are followed by a reduction of underlying allergen-specific Th2 cell-driven responses to the allergens. Tolerance induction takes place through the desensitization of effector cells and stimulation of regulatory T cells that show their effects by mechanisms involving cell-cell cross-talk, but also other mechanisms, e.g., by the production of immunomodulatory cytokines such as, e.g., IL-10 and TGF-beta. From a personalized medical perspective, there is a need for clinical biomarkers of value in selecting responders and optimizing patient care during AIT. Also, a deeper understanding of underlying mechanistic processes will improve AIT's future outcomes. In this paper, the current knowledge of mechanisms in AIT is reviewed with a special focus on biomarkers of this therapy. [ABSTRACT FROM AUTHOR]

Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component‐resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decisions. [ABSTRACT FROM AUTHOR]

Allergen-specific immunotherapy (AIT) is a potent and precise immune tolerance-inducing treatment toward specific proteins. AIT induces regulatory cells including allergen-specific Treg, Breg and DCreg. Also, AIT induces allergen-specific IgD and IgD constrains IgE-mediated basophil degranulation. [Extracted from the article]

Background: In previous studies with peripheral blood cells, platelet factors were found to be associated with severe allergic phenotypes. A reliable method yielding highly concentrated and pure platelet samples is usually not available for immunological studies. Plateletpheresis is widely used in the clinics for donation purposes. In this study, we designed a protocol based on plateletpheresis to obtain Platelet‐Rich Plasma (PRP), Platelet‐Poor Plasma (PPP) as well as CD3+ and CD14+ cells matched samples from a waste plateletpheresis product for immunological studies. Methods: Twenty‐seven subjects were voluntarily subjected to plateletpheresis. PRP, PPP and blood cell concentrate contained in a leukocyte reduction system chamber (LRSC) were obtained in this process. CD3+ and CD14+ cells were isolated from the LRSC by density‐gradient centrifugation and positive magnetic bead isolation. RNA was isolated from PRP, CD3+ and CD14+ cell samples and used for transcriptomic studies by Affymetrix. PRP and PPP samples were used for platelet protein quantification by multiplex assays. Results: A reliable high yield method to obtain matched samples of PRP, PPP, CD3+ and CD14+ from a single donor for RNA and protein analyses has been designed. The RNA quality indicators (RQI) routinely used for other cell types were not suitable for platelet RNA characterization. Despite this, the platelet RNA was valid for transcriptomic studies by Affymetrix, as platelet transcripts obtained in our previous studies were confirmed in PRP samples. Platelet samples were enriched in platelet factors as determined in protein multiplex analysis. Conclusions: We have developed a method that yields not only high content and pure platelet samples from a single donor but also CD3+ and CD14+ matched samples that can be used for RNA and protein analyses in immunological studies. [ABSTRACT FROM AUTHOR]

Allergic diseases and asthma are heterogenous chronic inflammatory conditions with several distinct complex endotypes. Both environmental and genetic factors can influence the development and progression of allergy. Complex pathogenetic pathways observed in allergic disorders present a challenge in patient management and successful targeted treatment strategies. The increasing availability of high‐throughput omics technologies, such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics allows studying biochemical systems and pathophysiological processes underlying allergic responses. Additionally, omics techniques present clinical applicability by functional identification and validation of biomarkers. Therefore, finding molecules or patterns characteristic for distinct immune‐inflammatory endotypes, can subsequently influence its development, progression, and treatment. There is a great potential to further increase the effectiveness of single omics approaches by integrating them with other omics, and nonomics data. Systems biology aims to simultaneously and longitudinally understand multiple layers of a complex and multifactorial disease, such as allergy, or asthma by integrating several, separated data sets and generating a complete molecular profile of the condition. With the use of sophisticated biostatistics and machine learning techniques, these approaches provide in‐depth insight into individual biological systems and will allow efficient and customized healthcare approaches, called precision medicine. In this EAACI Position Paper, the Task Force "Omics technologies in allergic research" broadly reviewed current advances and applicability of omics techniques in allergic diseases and asthma research, with a focus on methodology and data analysis, aiming to provide researchers (basic and clinical) with a desk reference in the field. The potential of omics strategies in understanding disease pathophysiology and key tools to reach unmet needs in allergy precision medicine, such as successful patients' stratification, accurate disease prognosis, and prediction of treatment efficacy and successful prevention measures are highlighted. [ABSTRACT FROM AUTHOR]

The integrin α4β1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides co- stimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of α4β1 during the formation of the immune synapse is currently unknown. Here, we show that α4β1 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramo- lecular activation complex. However, when conjugates are formed in the presence of anti-α4 antibodies, VLA-4 colocalizes with the CD3-δ chain at the center of the synapse. In addition, antibody engagement of α4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4+ T cell differentiation and naïve T cell priming by dendritic cells. The in vivo administration of anti-α4 integrin antibodies also induces an immune deviation to Thi response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of α4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions. [ABSTRACT FROM AUTHOR]

Background: Sublingual allergen‐specific immunotherapy (SLIT) intervention improves the control of grass pollen allergy by maintaining allergen tolerance after cessation. Despite its widespread use, little is known about systemic effects and kinetics associated to SLIT, as well as the influence of the patient sensitization phenotype (Mono‐ or Poly‐sensitized). In this quest, omics sciences could help to gain new insights to understand SLIT effects. Methods: 47 grass‐pollen‐allergic patients were enrolled in a double‐blind, placebo‐controlled, multicenter trial using GRAZAX® during 2 years. Immunological assays (sIgE, sIgG4, and ISAC) were carried out to 31 patients who finished the trial. Additionally, serum and PBMCs samples were analyzed by metabolomics and transcriptomics, respectively. Based on their sensitization level, 22 patients were allocated in Mono‐ or Poly‐sensitized groups, excluding patients allergic to epithelia. Individuals were compared based on their treatment (Active/Placebo) and sensitization level (Mono/Poly). Results: Kinetics of serological changes agreed with those previously described. At two years of SLIT, there are scarce systemic changes that could be associated to improvement in systemic inflammation. Poly‐sensitized patients presented a higher inflammation at inclusion, while Mono‐sensitized patients presented a reduced activity of mast cells and phagocytes as an effect of the treatment. Conclusions: The most relevant systemic change detected after two years of SLIT was the desensitization of effector cells, which was only detected in Mono‐sensitized patients. This change may be related to the clinical improvement, as previously reported, and, together with the other results, may explain why clinical effect is lost if SLIT is discontinued at this point. [ABSTRACT FROM AUTHOR]

Background: Despite all the efforts made up to now, the reasons that facilitate a protein becoming an allergen have not been elucidated yet. Alt a 1 protein is the major fungal allergen responsible for chronic asthma, but little is known about its immunological activity. Our main purpose was to investigate the ligand‐dependent interactions of Alt a 1 in the human airway epithelium. Methods: Alt a 1 with and without its ligand (holo‐ and apo‐ forms) was incubated with the pulmonary epithelial monolayer model, Calu‐3 cells. Allergen transport and cytokine production were measured. Pull‐down and immunofluorescence assays were employed to identify the receptor of Alt a 1 using the epithelial cell model and mouse tissues. Receptor‐allergen‐ligand interactions were analyzed by computational modeling. Results: The holo‐form could activate human monocytes, PBMCs, and polarized airway epithelial (Calu‐3) cell lines. The allergen was also transported through the monolayer, without any alteration of the epithelial integrity (TEER). Alt a 1 also induced the production of proinflammatory IL8 and specific epithelial cytokines (IL33 and IL25) by Calu‐3 cells. The interaction between epithelial cells and holo‐Alt a 1 was found to be mediated by the SLC22A17 receptor, and its recognition of Alt a 1 was explained in structural terms. Conclusions: Our findings identified the Alt a 1 ligand as a central player in the interaction of the allergen with airway mucosa, shedding light into its potential role in the immunological response, while unveiling its potential as a new target for therapy intervention. [ABSTRACT FROM AUTHOR]

Numbers of langerin+ cells among the experimental groups were similar; however, Fc RI expression in these cells tended to be higher in the oral epithelium of allergic patients (data not shown). To our knowledge, this is the first study describing an affected oral mucosa in the absence of food allergy and opens new ways of understanding barrier alterations associated with respiratory allergy. A disrupted barrier could be responsible for the progression to food allergy when the affected oral mucosa gets in direct contact with a trigger.[2] In fact, many food allergies are associated with previous respiratory sensitizations (PR10, lipid transfer proteins, profilins).[10]. [Extracted from the article]

The potential of precision medicine in allergy and asthma has only started to be explored. A significant clarification in the pathophysiology of rhinitis, chronic rhinosinusitis, asthma, food allergy and drug hypersensitivity was made in the last decade. This improved understanding led to a better classification of the distinct phenotypes and to the discovery of new drugs such as biologicals, targeting phenotype‐specific mechanisms. Nevertheless, many conditions remain poorly understood such as non‐eosinophilic airway diseases or non‐IgE–mediated food allergy. Moreover, there is a need to predict the response to specific therapies and the outcome of drug and food provocations. The identification of patients at risk of progression towards severity is also an unmet need in order to establish adequate preventive or therapeutic measures. The implementation of precision medicine in the clinical practice requires the identification of phenotype‐specific markers measurable in biological matrices. To become useful, these biomarkers need to be quantifiable by reliable systems, and in samples obtained in an easy, rapid and cost‐efficient way. In the last years, significant research resources have been put in the identification of valid biomarkers for asthma and allergic diseases. This review summarizes these recent advances with focus on the biomarkers with higher clinical applicability. [ABSTRACT FROM AUTHOR]

To investigate mechanisms conferring susceptibility or resistance to renal ischemia, we used two rat strains known to exhibit different responses to ischemia–reperfusion. We exposed proximal tubule cells isolated from Sprague Dawley or Brown Norway rats, to a protocol of hypoxia, followed by reoxygenation in vitro. The cells isolated from both rat strains exhibited comparable responses in the disruption of intercellular adhesions and cytoskeletal damage. In vivo, after 24 h of reperfusion, both strains showed similar degrees of injury. However, after 7 days of reperfusion, renal function and tubular structure almost completely recovered and inflammation resolved, but only in Brown Norway rats. Hypoxia-inducible factor-dependent gene expression, ERK1/2, and Akt activation were different in the two strains. Inflammatory mediators MCP-1, IL-10, INF-γ, IL-1β, and TNF-α were similarly induced at 24 h in both strains but were downregulated earlier in Brown Norway rats, which correlated with shorter NFκB activation in the kidney. Moreover, VLA-4 expression in peripheral blood lymphocytes and VCAM-1 expression in kidney tissues were initially similar at 24 h but reached basal levels earlier in Brown Norway rats. The faster resolution of inflammation in Brown Norway rats suggests that this strain might be a useful experimental model to determine the mechanisms that promote repair of renal ischemia–reperfusion injury. [ABSTRACT FROM AUTHOR]

Abstract: α-defensins1–3 are potent antimicrobial molecules that also link innate and adaptive immunity, depending on the concentration range. However, their effects on the biology of human DCs remain largely unknown. We analyzed the impact of different concentrations of α-defensins1–3 on the maturation and differentiation of monocyte-derived DCs (MDDCs). Low doses of α-defensins1–3 up-regulated CD83, CD86 and HLA-DR expression, increased TNF-α, IL-1β, IL-12p40, IL-10 and IL-8 secretion, and slightly augmented allostimulatory capacity. By contrast, high doses down-regulated CD86 and HLA-DR expression, TNF-α, IL-1β, IL-12p40 and IL-10 secretion and allostimulatory capacity, whereas strongly up-regulated IL-8. Furthermore, during the MDDC differentiation process, high doses of α-defensins1–3 affected CD14, CD11c and CD86 expression and strongly up-regulated IL-8. Results suggest that α-defensins1–3 might modulate the maturation and differentiation of MDDCs in vivo and therefore could be of special interest in the field of vaccine development. [Copyright &y& Elsevier]

Emerging evidence suggests that platelets, cytoplasmic fragments derived from megakaryocytes, can no longer be considered just as mediators in hemostasis and coagulation processes, but as key modulators of immunity. Platelets have received increasing attention as the emergence of new methodologies has allowed the characterization of their components and functions in the immune continuum. Platelet activation in infectious and allergic lung diseases has been well documented and associated with bacterial infections reproduced in several animal models of pulmonary bacterial infections. Direct interactions between platelets and bacteria have been associated with increased pulmonary platelet accumulation, whereas bacterial-derived toxins have also been reported to modulate platelet function. Recently, platelets have been found extravascular in the lungs of patients with asthma, and in animal models of allergic lung inflammation. Their ability to interact with immune and endothelial cells and secrete immune mediators makes them one attractive target for biomarker identification that will help characterize their contribution to lung diseases. Here, we present an original review of the last advances in the platelet field with a focus on the contribution of platelets to respiratory infections and allergic-mediated diseases. [ABSTRACT FROM AUTHOR]