Инвестиционные и маркетинговые изменения на рынке мобильной связи Украины

PURPOSE OF REVIEW: Despite reaching high percentages of desensitization using allergen-specific immunotherapy (SIT) in patients with food allergy, recent studies suggest only a low number of patients to reach persistent clinical tolerance. This review describes current developments in strategies to improve safety and long-term efficacy of SIT. RECENT FINDINGS: Modified allergens or tolerogenic peptides, ultimately optimized for human leukocyte antigen background of the patient, are explored for tolerance induction, whereas anti-IgE antibody (Omalizumab) may be used to facilitate SIT safety. Adjunct therapies to enhance efficacy may make use of TH1 polarizing agents, for example, CpG-oligodeoxynucleotides combined with modified allergen packaged in nanoparticles. Preclinical studies showed insulin-like growth factor-2, intravenous immunoglobulin, Tregitopes or allergen encased oligomannose-coated liposomes capable of inducing regulatory T-cells, recognized for their importance in clinical tolerance induction. Dietary intervention strategies utilizing herbal formula 2, VSL#3, nondigestible short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) plus Bifidobacterium breve M-16V or n-3 long-chain polyunsaturated fatty acids may facilitate safety and/or a favourable milieu for tolerance induction. SUMMARY: Combining SIT using (adapted) allergens or tolerogenic peptides with adjunct therapy may be essential to improve safety and/or efficacy. Beyond using targeted approaches, specific dietary components may be explored to reduce side-effects and support clinical tolerance induction by SIT

Возможности использования ксеноселезенки в клинической практике

Рассмотрена проблема применения ксеноселезенки в клинике. Показана целесообразность применения криобиологических технологий для получения биологически активных экстрактов из фрагментов ксеноселезенки. Разработан такой экстракт, определены его биофармацевтические свойства и клиническая эффективность при эндобронхиальном введении больным с абсцессами легких.The problem of xenospleen use in clinical practice is discussed. Reasonability of application of cryobiological technologies to obtain biologically active extracts from xenospleen fragments is shown. The extract has been developed, its biopharmaceutical properties and clinical efficacy at endobronchial administration in patients with lung abscess is shown

Oral pretreatment with β-lactoglobulin derived peptide and CpG co-encapsulated in PLGA nanoparticles prior to sensitizations attenuates cow's milk allergy development in mice

Cow's milk allergy is a common food allergy among infants. Improved hygiene conditions and loss of microbial diversity are associated with increased risk of allergy development. The intestinal immune system is essential for oral tolerance induction. In this respect, bacterial CpG DNA is known to drive Th1 and regulatory T-cell (Treg) development via Toll-Like-Receptor 9 (TLR-9) signaling, skewing away from the allergic Th2 phenotype. We aimed to induce allergen specific tolerance via oral delivery of poly (lactic-co-glycolic acid) nanoparticles (NP) co-encapsulated with a selected β-lactoglobulin derived peptide (BLG-Pep) and TLR-9 ligand CpG oligodeoxynucleotide (CpG). In vivo, 3-4-week-old female C3H/HeOuJ mice housed in individually ventilated cages received 6-consecutive-daily gavages of either PBS, whey, BLG-Pep/NP, CpG/NP, a mixture of BLG-Pep/NP plus CpG/NP or co-encapsulated BLG-Pep+CpG/NP, before 5-weekly oral sensitizations with whey plus cholera toxin (CT) or only CT (sham) and were challenged with whey 5 days after the last sensitization. The co-encapsulated BLG-Pep+CpG/NP pretreatment, but not BLG-Pep/NP, CpG/NP or the mixture of BLG-Pep/NP plus CpG/NP, prevented the whey-induced allergic skin reactivity and prevented rise in serum BLG-specific IgE compared to whey-sensitized mice. Importantly, co-encapsulated BLG-Pep+CpG/NP pretreatment reduced dendritic cell (DC) activation and lowered the frequencies of PD-L1+ DC in the mesenteric lymph nodes compared to whey-sensitized mice. By contrast, co-encapsulated BLG-Pep+CpG/NP pretreatment increased the frequency of splenic PD-L1+ DC compared to the BLG-Pep/NP plus CpG/NP recipients, in association with lower Th2 development and increased Treg/Th2 and Th1/Th2 ratios in the spleen. Oral administration of PLGA NP co-encapsulated with BLG-Pep and CpG prevented rise in serum BLG-specific IgE and symptom development while lowering splenic Th2 cell frequency in these mice which were kept under strict hygienic conditions

Long Chain Polyunsaturated Fatty Acids (LCPUFAs) in the Prevention of Food Allergy

N-3 long chain polyunsaturated fatty acids (LCPUFAs) are considered to possess protective properties for human health by impacting on immunological reactions. An “inflammation-suppressive” effect appears to be the common denominator of the beneficial effects of most of these dietary components which may protect against the development of chronic immune disorders such as (food) allergy. LCPUFAs, especially n-3 LCPUFAs, have been shown to interact with both the sensitization as well as the effector phase in food allergy in pre-clinical models. In this review, we explore the anti-allergic properties of LCPUFAs by providing an overview of clinical, in vivo and in vitro studies. Furthermore, we discuss the susceptibility of LCPUFAs to lipid oxidation and possible strategies to support the efficacy of LCPUFAs in reducing the allergy risk by using additional components with anti-oxidative and anti-inflammatory capacities such as the flavonoid quercetin. Finally, we propose new strategies to prevent (food) allergy using combinations of LCPUFAs and additional nutrients in diets or supplements, and postulate to investigate the use of LCPUFAs in allergic symptom relief

Ovalbumin-Induced Epithelial Activation Directs Monocyte-Derived Dendritic Cells to Instruct Type 2 Inflammation in T Cells Which Is Differentially Modulated by 2'-Fucosyllactose and 3-Fucosyllactose

Allergic sensitization starts with epithelial cell activation driving dendritic cells (DCs) to instruct T helper 2 (Th2) cell polarization. Food allergens trigger intestinal epithelial cell (IEC) activation. Human milk oligosaccharides may temper the allergic phenotype by shaping mucosal immune responses.We investigated in vitro mucosal immune development after allergen exposure by combining ovalbumin (OVA)-preexposed IEC with monocyte-derived DCs (OVA-IEC-DCs) and subsequent coculture of OVA-IEC-DCs with Th cells. IECs were additionally preincubated with 2'FL or 3FL.OVA activation increased IEC cytokine secretion. OVA-IEC-DCs instructed both IL13 (p < 0.05) and IFNγ (p < 0.05) secretion from Th cells. 2'FL and 3FL permitted OVA-induced epithelial activation, but 2'FL-OVA-IEC-DCs boosted inflammatory and regulatory T-cell development. 3FL-OVA-IEC lowered IL12p70 and IL23 in DCs and suppressed IL13 (p < 0.005) in T cells, while enhancing IL17 (p < 0.001) and IL10 (p < 0.005).These results show that OVA drives Th2- and Th1-type immune responses via activation of IECs in this model. 2'FL and 3FL differentially affect OVA-IEC-driven immune effects. 2'FL boosted overall T-cell OVA-IEC immunity via DC enhancing inflammatory and regulatory responses. 3FL-OVA-IEC-DCs silenced IL13, shifting the balance towards IL17 and IL10.This model demonstrates the contribution of IEC to OVA Th2-type immunity. 2'FL and 3FL modulate the OVA-induced activation in this novel model to study allergic sensitization

Live Cell Imaging by Förster Resonance Energy Transfer Fluorescence to Study Trafficking of PLGA Nanoparticles and the Release of a Loaded Peptide in Dendritic Cells

Our previous study demonstrated that a selected β-lactoglobulin-derived peptide (BLG-Pep) loaded in poly(lactic- co-glycolic acid) (PLGA) nanoparticles protected mice against cow's milk allergy development. However, the mechanism(s) responsible for the interaction of the peptide-loaded PLGA nanoparticles with dendritic cells (DCs) and their intracellular fate was/were elusive. Förster resonance energy transfer (FRET), a distance-dependent non-radioactive energy transfer process mediated from a donor to an acceptor fluorochrome, was used to investigate these processes. The ratio of the donor (Cyanine-3)-conjugated peptide and acceptor (Cyanine-5) labeled PLGA nanocarrier was fine-tuned for optimal (87%) FRET efficiency. The colloidal stability and FRET emission of prepared NPs were maintained upon 144 h incubation in PBS buffer and 6 h incubation in biorelevant simulated gastric fluid at 37 °C. A total of 73% of Pep-Cy3 NP was internalized by DCs as quantified using flow cytometry and confirmed using confocal fluorescence microscopy. By real-time monitoring of the change in the FRET signal of the internalized peptide-loaded nanoparticles, we observed prolonged retention (for 96 h) of the nanoparticles-encapsulated peptide as compared to 24 h retention of the free peptide in the DCs. The prolonged retention and intracellular antigen release of the BLG-Pep loaded in PLGA nanoparticles in murine DCs might facilitate antigen-specific tolerance induction

Oral pretreatment with β-lactoglobulin derived peptide and CpG co-encapsulated in PLGA nanoparticles prior to sensitizations attenuates cow’s milk allergy development in mice

Cow’s milk allergy is a common food allergy among infants. Improved hygiene conditions and loss of microbial diversity are associated with increased risk of allergy development. The intestinal immune system is essential for oral tolerance induction. In this respect, bacterial CpG DNA is known to drive Th1 and regulatory T-cell (Treg) development via Toll-Like-Receptor 9 (TLR-9) signaling, skewing away from the allergic Th2 phenotype. We aimed to induce allergen specific tolerance via oral delivery of poly (lactic-co-glycolic acid) nanoparticles (NP) co-encapsulated with a selected β-lactoglobulin derived peptide (BLG-Pep) and TLR-9 ligand CpG oligodeoxynucleotide (CpG). In vivo, 3-4-week-old female C3H/HeOuJ mice housed in individually ventilated cages received 6-consecutive-daily gavages of either PBS, whey, BLG-Pep/NP, CpG/NP, a mixture of BLG-Pep/NP plus CpG/NP or co-encapsulated BLG-Pep+CpG/NP, before 5-weekly oral sensitizations with whey plus cholera toxin (CT) or only CT (sham) and were challenged with whey 5 days after the last sensitization. The co-encapsulated BLG-Pep+CpG/NP pretreatment, but not BLG-Pep/NP, CpG/NP or the mixture of BLG-Pep/NP plus CpG/NP, prevented the whey-induced allergic skin reactivity and prevented rise in serum BLG-specific IgE compared to whey-sensitized mice. Importantly, co-encapsulated BLG-Pep+CpG/NP pretreatment reduced dendritic cell (DC) activation and lowered the frequencies of PD-L1+ DC in the mesenteric lymph nodes compared to whey-sensitized mice. By contrast, co-encapsulated BLG-Pep+CpG/NP pretreatment increased the frequency of splenic PD-L1+ DC compared to the BLG-Pep/NP plus CpG/NP recipients, in association with lower Th2 development and increased Treg/Th2 and Th1/Th2 ratios in the spleen. Oral administration of PLGA NP co-encapsulated with BLG-Pep and CpG prevented rise in serum BLG-specific IgE and symptom development while lowering splenic Th2 cell frequency in these mice which were kept under strict hygienic conditions

Diversity of Human Milk Oligosaccharides and Effects on Early Life Immune Development

One of the well-known features of human milk, is the capacity to protect against the risk and impact of neonatal infections, as well as to influence the onset of allergic and metabolic disease manifestations. The major objective of this review is to provide a detailed overview regarding the role of human milk, more specifically the diversity in human milk oligosaccharides (HMOS), on early life immune development. Novel insights in immune modulatory effects of HMOS obtained by in vitro as well as in vivo studies, adds to the understanding on how early life nutrition may impact immune development. Extensive description and analysis of single HMOS contributing to the diversity within the composition provided during breastfeeding will be discussed with specific emphasis on immune development and the susceptibility to neonatal and childhood infections

The Combination Therapy of Dietary Galacto-Oligosaccharides With Budesonide Reduces Pulmonary Th2 Driving Mediators and Mast Cell Degranulation in a Murine Model of House Dust Mite Induced Asthma

Background: Dietary non-digestible galacto-oligosaccharides (GOS) suppress allergic responses in mice sensitized and challenged with house dust mite (HDM). Budesonide is the standard therapy for allergic asthma in humans but is not always completely effective.Aim: To compare the efficacy of budesonide or different doses of GOS alone or with a combination therapy of budesonide and GOS on HDM-allergic responses in mice.Methods:BALB/c mice were sensitized and challenged with HDM, while fed a control diet or a diet supplemented with 1 or 2.5 w/w% GOS, and either or not oropharyngeally instilled with budesonide. Systemic and local inflammatory markers, such as mucosal mast cell protease-1 (mMCP-1) in serum, pulmonary CCL17, CCL22, and IL-33 concentrations and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) were determined.Results: Budesonide or GOS alone suppressed the number of eosinophils in the BALF of HDM allergic mice whereas budesonide either or not combined with GOS lowered both eosinophil and lymphocyte numbers in the BALF of HDM-allergic mice. Both 1 w/w% and 2.5 w/w% GOS and/or budesonide suppressed serum mMCP-1 concentrations. However, budesonide nor GOS alone was capable of reducing Th2 driving chemokines CCL17, CCL22 and IL-33 protein levels in supernatants of lung homogenates of HDM allergic mice, whereas the combination therapy did. Moreover, IL-13 concentrations were only significantly suppressed in mice treated with budesonide while fed GOS. A similar tendency was observed for the frequency of GATA3+CD4+ Th2 and CD4+RORγt+ Th17 cells in the lungs of the allergic mice.Conclusion: Dietary intervention using GOS may be a novel way to further improve the efficacy of anti-inflammatory drug therapy in allergic asthma by lowering Th2 driving mediators and mast cell degranulation