WO2017060498A1 - Acide n-glycolyneuraminique pour la prévention ou le traitement de l'asthme ou de l'allergie - Google Patents

Acide n-glycolyneuraminique pour la prévention ou le traitement de l'asthme ou de l'allergie Download PDF

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WO2017060498A1
WO2017060498A1 PCT/EP2016/074108 EP2016074108W WO2017060498A1 WO 2017060498 A1 WO2017060498 A1 WO 2017060498A1 EP 2016074108 W EP2016074108 W EP 2016074108W WO 2017060498 A1 WO2017060498 A1 WO 2017060498A1
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neu5gc
allergy
asthma
allergic
prevention
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PCT/EP2016/074108
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English (en)
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Roger LAUENER
Remo Frei
Caroline RODUIT
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Universität Zürich
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • N-glycolyneuraminic acid for the prevention or treatment of asthma and allergy
  • the present invention relates to the prevention or treatment of asthma and allergy using N-glycolyneuraminic acid (Neu5Gc).
  • the invention further relates to dietary compositions comprising Neu5Gc. Background of the invention
  • N-glycolyneuraminic acid (CAS No. 1 1 13-83-3) is a sialic acid composed of nine carbon sugars found at the most outer unit of the cellular glycocalyx and on secreted glycoproteins in most mammalian cells.
  • CMAH CMP-Neu5Ac hydroxylase
  • Humans are able to take up Neu5Gc via fluid pinocytosis and a specific lysosomal transporter and incorporate it into newly synthesized glycoproteins.
  • Known dietary sources of Neu5Gc are red meat and cow's milk products. Humans mount a humoral immune response upon exposure to non-human mammalian cells by producing anti-Neu5Gc immunoglobulins.
  • Levels of antibodies reactive to Neu5Gc in human serum samples may serve as a marker for environmental exposure related to Neu5Gc. Such exposure may be animal contact such as presence in stables or contact to pets, or consumption of animal-derived foods such as cow's milk or meat.
  • Neu5Gc has pro-inflammatory effects and even induces colitis.
  • Mice lacking the enzyme CMP-Neu5Ac hydroxylase (CMAH) due to a knock-out of the respective gene, which are not able to synthesize Neu5Gc from the precursor N- acetylneuraminic acid (Neu5Ac) have hyperactive B and T cells.
  • CMAH CMP-Neu5Ac hydroxylase
  • mononuclear cells all types of T helper cells, as well as both pro- and anti-inflammatory cytokines (e.g. TNF-a and IL10, respectively) were induced by Neu5Gc. If isolated cells were treated with Neu5Gc, however, the immunoregulatory T cell population T reg and the regulatory dendritic cells were induced. Altogether, the data concerning Neu5GC are inconsistent and contradictory.
  • the present invention focuses on the prevention or treatment of allergic and inflammatory diseases, in particular the prevention or treatment of asthma and allergy in children.
  • the invention is based on new findings, demonstrating that Neu5Gc has in vivo anti- inflammatory/immunoregulatory effects and thus can be applied to prevent and/or treat inflammatory and allergic diseases. Summary of the invention
  • the present invention relates to a method of preventing or treating allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy, using Neu5Gc, in particular in children.
  • the invention also relates to the use of Neu5Gc in prevention or treatment of allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy, and to the manufacture of medicaments for preventing or treating allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy, and to a food product enriched with Neu5Gc that is useful in said prevention or treatment, and to the manufacture of such a food product.
  • Neu5Gc is provided for use in the prevention or treatment of allergic and inflammatory diseases, including, but not limited to atopic dermatitis/eczema, non-atopic dermatitis/eczema, rhinoconjunctivitis, asthma, food allergy, drug allergy, inflammatory diseases of the skin, the lung, the gastrointestinal tract, the central and peripheral nervous system, musculoskeletal diseases and infectious disease.
  • allergic and inflammatory diseases including, but not limited to atopic dermatitis/eczema, non-atopic dermatitis/eczema, rhinoconjunctivitis, asthma, food allergy, drug allergy, inflammatory diseases of the skin, the lung, the gastrointestinal tract, the central and peripheral nervous system, musculoskeletal diseases and infectious disease.
  • Neu5Gc is provided for use in a method for reducing the risk of development of allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy, of the baby in infancy or early childhood by providing the compound to the mother during pregnancy or in the first months after giving birth.
  • allergic and inflammatory diseases particularly allergic airway inflammatory disease, asthma and/or allergy
  • composition comprising Neu5Gc is provided for use in the prevention or treatment of allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy.
  • One aspect of the invention relates to a method of preventing or treating a condition selected from allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy, comprising administering Neu5Gc in a quantity effective against said condition to a patient in need thereof, for example to a human requiring such treatment.
  • a condition selected from allergic and inflammatory diseases particularly allergic airway inflammatory disease, asthma and/or allergy
  • One aspect of the invention relates to a nutritional composition
  • a nutritional composition comprising a source of protein, a source of fat and a source of carbohydrate, and supplemented with Neu5Gc.
  • Figure 1 Association between anti-Neu5Gc IgG levels (tertile) and wheeze or asthma (a) Cross-sectional, PARSIFAL study: adjusted odds ratio for wheezing and asthma in school-age children comparing tertiles of anti-Neu5Gc IgG levels with the lowest tertile as the reference, (b) Longitudinal, PASTURE study: adjusted odds ratio for wheezing and asthma at age of 6 years comparing tertiles of anti-Neu5Gc IgG levels with the lowest tertile as the reference, stratified by atopic status. Odds ratio was adjusted for farmer, centre and atopic parents, sex; aOR and 95% confidence intervals are shown; aOR, adjusted odds ratio.
  • CMAH-deficient mice display more severe Al than wild-type mice, (a) Airway resistance in response to 30 mg of methacholine. Rn, resistance, (b) Total and differential cell counts in BAL. Eos, eosinophils; Neut, neutrophils; Mac, macrophages; Lymph, lymphocytes, (c) Total and ovalbumin-specific IgE levels in serum, (d) Quantification of lung CD1 1 c+ dendritic cells and their RALDH enzyme activity.
  • Control not sensitized but challenged with the allergen
  • Al sensitized and challenged with the allergen
  • Each dot represents an individual mouse
  • n 4-6; Mean and SEM; Mann Whitney test
  • Al Airway- inflammation
  • BAL Bronchoalveolar lavage
  • CMAH CMP-Neu5Ac hydroxylase
  • RALDH Retinaldehyde dehydrogenase.
  • Figure 3 Oral application of Neu5Gc to CMAH-deficient mice reduced the severity of an ovalbumin-dependent Al model, (a) Airway resistance in response to methacholine. Rn, resistance, (b) Total and differential cell counts in BAL. Eos, eosinophils; Neut, neutrophils; Mac, macrophages; Lymph, lymphocytes, (c) Total and ovalbumin-specific IgE levels in serum, (d) Quantification of cytokines secretion by lung CD3+/CD4+ T helper cells, (e) Quantification 683 of lung CD25+Foxp3+ TREG cells and their IL-10 secretion.
  • Figure 5 In vitro stimulation of human MDDC and T helper cells with Neu5Gc induced a regulatory phenotype. (a) Expression of I DO and RALDH2 genes and secretion of IL-10 by human MDDC stimulated with Neu5Gc. (b) T helper cell differentiation induced by Neu5Gc.
  • the present invention relates to a method of preventing or treating allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy, comprising administering Neu5Gc to a patient in need thereof, and the use of Neu5Gc in said prevention or treatment and in the manufacture of medicaments for preventing or treating allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy.
  • the present invention relates furthermore to the use of a food product enriched with Neu5Gc in said prevention or treatment and in the manufacture of such a food product.
  • N-glycolylneuraminic acid (CAS No. 1 1 13-83-3) is provided for use in the prevention or treatment of allergic and inflammatory diseases, including, but not limited to atopic dermatitis/eczema, non-atopic dermatitis/eczema, rhinoconjunctivitis, asthma, food allergy, drug allergy, inflammatory diseases of the skin, the lung, the gastrointestinal tract, the central and peripheral nervous system, musculoskeletal diseases and infectious disease.
  • allergic and inflammatory diseases including, but not limited to atopic dermatitis/eczema, non-atopic dermatitis/eczema, rhinoconjunctivitis, asthma, food allergy, drug allergy, inflammatory diseases of the skin, the lung, the gastrointestinal tract, the central and peripheral nervous system, musculoskeletal diseases and infectious disease.
  • Neu5Gc is provided for use in the prevention or treatment of allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy.
  • allergic and inflammatory diseases particularly allergic airway inflammatory disease, asthma and/or allergy.
  • asthma or allergy manifests itself as wheezing.
  • Neu5Gc is provided for use in the prevention or treatment of allergic and inflammatory diseases including, but not limited to atopic dermatitis/eczema, non-atopic dermatitis/eczema, rhinoconjunctivitis, asthma, food allergy, drug allergy, inflammatory diseases of the skin, the lung, the gastrointestinal tract, the central and peripheral nervous system, musculoskeletal diseases and infectious disease in children, particularly during the first year of life.
  • allergic and inflammatory diseases including, but not limited to atopic dermatitis/eczema, non-atopic dermatitis/eczema, rhinoconjunctivitis, asthma, food allergy, drug allergy, inflammatory diseases of the skin, the lung, the gastrointestinal tract, the central and peripheral nervous system, musculoskeletal diseases and infectious disease in children, particularly during the first year of life.
  • Neu5Gc is provided by oral administration, particularly for any one of the above indications.
  • Neu5Gc is provided as a dosage form which is a nutritional supplement or pharmaceutical formulation.
  • Neu5Gc is administered in a dosage of 0,1 to 1000 mg/kg patient weight, particularly 10-100 mg/kg patient weight.
  • Neu5Gc is administered once or twice per day.
  • composition comprising Neu5Gc is provided for use in the prevention or treatment of allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy.
  • the composition may be a nutritional product for administration to an infant, such as an infant formula or a human milk fortifier.
  • infant formula means a composition that satisfies the nutrient requirements of an infant by being a substitute for human milk.
  • human milk fortifier means a composition which can be added to human milk to enhance the nutritional value of the human milk.
  • the nutritional supplement may be a product for a full-term infant, a preterm infant, a low- birth-weight infant, or a very-low-birth-weight infant.
  • preterm or “preterm infant” may include low-birth-weight infants or very-low-birth weight infants.
  • Low-birth-weight infants are those born from about 32 to about 37 weeks of gestation or weighing from about 1500 to about 2500 grams at birth.
  • Very-low-birth-weight infants are those born before about 32 weeks of gestation or weighing less than about 1500 grams at birth.
  • preterm infants may include infants born before about 37 weeks gestation and/or those weighing less than about 2500 grams at birth.
  • Neu5Gc-enriched food products can be administered to adults, in particular to pregnant women, reducing the risk of development asthma or allergy of the baby in infancy or early childhood.
  • the nutritional supplement for use according to the present invention may comprise a source of protein.
  • Any suitable dietary protein may be used for example animal proteins (such as milk proteins, meat proteins and egg proteins); vegetable proteins (such as soy protein, wheat protein, rice protein, and pea protein); mixtures of free amino acids; or combinations thereof.
  • the composition may also contain a source of carbohydrates and a source of fat.
  • One aspect of the invention relates to a method of preventing or treating allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy, comprising administering Neu5Gc in a quantity effective against said allergic and inflammatory diseases to a patient in need thereof, for example to a human requiring such treatment.
  • the treatment may be for prophylactic or therapeutic purposes.
  • the dosage of the active ingredient depends upon the age, weight, and individual condition, the individual pharmacokinetic data, the mode of administration, and whether the administration is for prophylactic or therapeutic purposes.
  • the daily dose administered is approximately 0.1 to 1000 mg/kg, preferably approximately 10 to 100 mg/kg of Neu5Gc.
  • the daily dose administered is approximatively 0.1 to 1000 mg/kg, preferably approximatively 10 to 100 mg/kg of Neu5Gc.
  • the Neu5Gc content in the pharmaceutical composition is within the range of 0.25 mg - 375 mg per dosage unit. In certain embodiments, the Neu5Gc content in the pharmaceutical composition is 0.25 mg - 250 mg. In certain embodiments, the Neu5Gc content in the pharmaceutical composition is 2.5 mg - 250 mg. In certain embodiments, the Neu5Gc content in the pharmaceutical composition is 2.5 mg - 125 mg. In certain embodiments, the Neu5Gc content in the pharmaceutical composition is 2.5 mg - 100 mg or 2.5 mg - 75 mg/dosage unit.
  • compositions of Neu5Gc for parenteral administration preference is given to the use of solutions of Neu5Gc, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, which can be ready made or can be made up shortly before use.
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, viscosity-increasing agents, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
  • suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, and also binders, such as starches, cellulose derivatives and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, flow conditioners and lubricants, for example stearic acid or salts thereof and/or polyethylene glycol.
  • Tablet cores can be provided with suitable, optionally enteric, coatings. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules may contain the active ingredient in the form of granules, or dissolved or suspended in suitable liquid excipients, such as in oils.
  • Another aspect of the invention relates to the use of Neu5Gc in the manufacture of a medicament for use in the prevention or treatment of allergic and inflammatory diseases, particularly allergic airway inflammatory disease, asthma and/or allergy.
  • asthma in the context of the present specification refers to a condition of the respiratory tract characterized by widespread, reversible narrowing of the airways (bronchoconstriction) and increased sensitivity (hyperresponsiveness) of the airways to a variety of stimuli.
  • the familiar symptomology of asthma i.e., coughing, wheezing, chest tightness, dyspnoea, is caused by airway smooth muscle contraction, increased bronchial mucus secretion, and inflammation.
  • allergens in the context of the present invention refers to a hypersensitivity reaction initiated by immunological mechanisms. Symptoms arise in areas in contact with air, such as eyes, nose and lungs. Allergies can affect all age groups and can appear at any time, but it is the marked increase of allergies in children and young adults that is of particular concern. It is probable that environmental exposure to potential allergens early in life or during pregnancy has a pivotal role in the development of allergy.
  • topy in the context of the present invention refers to a predisposition toward, usually in childhood or adolescence, developing certain allergic hypersensitivity reactions in response to ordinary exposure to low dose of allergens.
  • Typical symptoms of patients with atopy are eczema (atopic dermatitis), hay fever (allergic rhinitis), and allergy-induced asthma (allergic asthma). Both environmental factors and hereditary components play a role in the development of atopy.
  • Neu5Gc can be administered alone or in combination with one or more other therapeutic agents known in the prevention or treatment of asthma and allergy.
  • administration of these can be staggered, or they can be given independently of one another, or in the form of a fixed combination.
  • Possible combination partners considered are short-chain fatty acids, probiotics or fibers.
  • Another embodiment of the invention relates to the use of a food product enriched with Neu5Gc in the prevention or treatment of asthma and allergy, particularly in children, and in the manufacture of such a food product.
  • the composition of the invention is appropriately targeted for different categories of patients, including young patients that develop symptoms of allergy or asthma.
  • Neu5Gc or compositions comprising same are administered to humans whose immune systems are still maturing. In such patients the effect of the composition is expected to be more intense or more rapid.
  • the composition is targeted at young patients below the age of 6 years, between birth and the age of 3 years or between birth and weaning. In certain embodiments, the composition is more specifically administered to patients during the weaning period and/or up to 12 months thereafter.
  • the weaning period is indeed important with regard to the invention as the infants are exposed to a variety of foods during the weaning period, while still undergoing maturation and re-organization of their immune system. Effective control of the allergic response is therefore of particular importance during that period.
  • the food product may be a nutritional composition, a nutraceutical, a drink, a food additive, or an infant nutrition.
  • it is a milk powder based product, an instant drink, a ready-to-drink formulation, a nutritional powder, a nutritional liquid, a dairy product, a cereal product, a beverage, water, coffee, cappuccino, a malt drink, a chocolate flavored drink, a culinary product, a soup, a topical cream, a suppository, a tablet or a syrup.
  • Milk may be any milk obtainable from animal or plant sources. Instead of milk, also milk derived protein fractions or colostrum may be used. Particularly preferred is low allergy milk or milk powder.
  • dairy product relates to milk-derived products, i.e. to products derived from animal milk, such as derived from species such as camel, cow, goat, horse, human, reindeer, sheep, water buffalo and yak.
  • the food product may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co- compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents, gel forming agents, antioxidants and antimicrobials. It may also contain an organic or inorganic carrier material suitable for oral administration as well as vitamins, mineral trace elements and other micronutrients.
  • protective hydrocolloids such as gums, proteins, modified starches
  • binders film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes
  • the effect of the Neu5Gc in food product is essentially dose dependent.
  • the exact amount of Neu5Gc to be provided will depend on the subject to be treated and on its condition. While in general every amount of Neu5Gc will produce beneficial effects, it is particularly preferred if the Neu5Gc is present in the food product in a amount 1 to 250 mg/g dry mass of the food product.
  • the Neu5Gc may be administered in a food product in a daily amount of approximately 0.1 to approximately 1000 mg/kg, preferably from approximately 10 to approximately 100 mg/kg body weight of the subject to be treated.
  • Neu5Gc is a molecule expressed on animal but not on human tissues, nor by microbes. Mice having the same knock-out in the Neu5Gc synthesis pathway as humans possess were more susceptible to allergic airway-inflammation and inflammatory bowel disease, which was reversed by oral administration of Neu5Gc.
  • Neu5Gc is a foreign molecule for humans, an antibody response is raised.
  • the inventors found in the context of two observational studies, namely PARSIFAL (Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Lifestyle) and PASTURE (Protection against Allergy-Study in Rural Environments), that the level of anti-Neu5Gc IgG was associated with contact to animals and with consumption of meat and that farmers' children have a much higher levels compared to non-farmers' (Table 1 ). Anti-Neu5Gc IgG levels therefore reflect exposure to non-human, non-microbial foreign tissue.
  • Atopy if either mother or father or both parents have asthma, hay fever or atopic dermatitis ever
  • Anti-Neu5Gc antibody quantification Levels of anti-Neu5Gc antibodies were determined by ELISA as previously described (Tangvoranuntakul et al. 2003, Proc Natl Acad Sci USA 100, 12045-12050). 500 ng per well Neu5Ac-polyacrylamide (PAA) or Neu5Gc-PAA (GlycoTech Corp, Gaithersburg, USA) were coated on a 96-well microtiter plate. After washing and blocking of the plate, 100 ⁇ of a 1 :10 dilution of the sera were incubated in duplicates on the plate.
  • PAA Neu5Ac-polyacrylamide
  • Neu5Gc-PAA Neu5Gc-PAA
  • Bound antibodies were detected using a horseradish- peroxidase (HRP)-conjugated mouse anti-human IgG (Sigma-Aldrich, Buchs, Switzerland). Measured values were normalized to a standard curve of normal human serum (Sigma-Aldrich, Buchs, Switzerland) measured on the same plate. For background correction of anti-Neu5Gc IgG levels, anti-Neu5Ac IgG levels were subtracted.
  • HRP horseradish- peroxidase
  • CMAH knock-out mice (Hedlund et al. 2007, Mol Cell Biol 27, 4340-4346) were a kind gift from Ajit Varki (University of California, San Diego, USA) and were bred at AO Research Institute in Davos.
  • Mice were housed in 5-6 animals per cage in individually ventilated cages in a 12/12h light/dark cycle with vegetarian food and water available ad libitum. Mice of different genotypes were co-housed for at least 2 weeks before the start of the experiments. All experimental procedures were carried out in accordance with Swiss law.
  • Ovalbumin model Mice were sensitized by intraperitoneal (i.p.) injection of 20 ⁇ g of Ovalbumin (OVA) grade VI (Sigma-Aldrich, Buchs, Switzerland) emulsified in 500 ⁇ g Alum (Pierce, Rockford, IL, USA) in 200 ⁇ sterile 0,9% isotonic sodium chloride (NaCI) on days 0, 7 and 21 , followed by 20 min 1 % OVA grade V (Sigma-Aldrich, Buchs, Switzerland) aerosol treatments on days 26, 27 and 28. Additional mice received daily 1 mg Neu5Gc by gavage starting 5 days prior to the first OVA injection. Analysis of mice occurred 24 h after last aerosol challenge.
  • OVA Ovalbumin
  • Bronchoalveolar lavage was performed 24 h after the last challenge using 1 ml PBS containing 1x protease inhibitor cocktail (Roche, Mannheim, Germany).
  • red blood cells were removed by re-suspending BAL cells in red blood cell lysis buffer (Sigma-Aldrich, Buchs, Switzerland) for 2 min at room temperature followed by washing in 1 ml PBS. Total number of lymphocytes was counted using a Neubauer counting chamber. For differential cell counts, cytospin preparations were fixed and stained with Diff-Quick (Merz & Dade AG, Dudingen, Switzerland).
  • Macrophages, lymphocytes, eosinophils, and neutrophils were identified by standard morphologic criteria and 100-200 cells were counted per cytospin.
  • SCID colitis Kjellev et al. 2006, Int Immunopharmacol, 1341-1354.
  • CD4+CD25- CD45RB+ cells were isolated from total spleen cells of BALB/c mice using two rounds of AutoMACS separation with reagents of Miltenyi Biotech (Bergisch Gladbach, Germany). 380 ⁇ 00 cells were i.p. injected into C.B 17 SCID mice. Control animals were injected with sodium chloride. The severity of the disease was assessed by loss of body weight and a symptom score comprising the injection site, breathing, activity, the fur condition, movement, body weight, and status of the feces.
  • Lung tissue cell isolation and flow cytometric analysis Lung tissue cell isolation and flow cytometric analysis.
  • the lung dissociation kit for mouse and a gentleMACSTM Miltenyi, Bergisch Gladbach, Germany
  • All flow cytometric analyses were performed on the Gallios Flow Cytometer (Beckman Coulter, Brea, USA).
  • Anti-I-A/I-E, anti-Ly6C, anti-CD1 1 b, anti-CD1 1 c, anti CD3 anti-CD19, anti-CD103, and anti-CD4 antibodies were obtained from BioLegend (San Diego, USA).
  • Anti-CD25, anti-Foxp3, anti-IL-10, anti-IL-17A, anti-IFN- ⁇ , and anti-IL-4 antibodies were obtained from eBioscience (Vienna, Austria). Cells were stained by the fixable viability dye eFlour780 (eBioscience Vienna, Austria). For intracellular cytokine staining, the cells were stimulated with PMA/lonomycin (50ng/ml and 500ng/ml) for 4 h at 37 °C and 5% C0 2 in the presence of Brefeldin solution (eBioscience, Vienna, Austria) to stop cytokine secretion. Cells were permeabilized with reagends from eBioscience (Vienna, Austria). To assess RALDH activity we used the ALDOFLOUR kit of STEMCELL technology (Grenoble, France).
  • Immunoglobulins Total immunoglobulins were assessed with a Milliplex kit (Merck Millipore, Billerica, USA). OVA-specific IgE levels in sera were measured by ELISA coated with OVA and detected with anti-lgE (BD Bioscience, New Jersey, USA).
  • Lung function measurements Mice were intubated under anesthesia and assessed using the flexiVent system (SCIREQ, Montreal, Canada). Lung resistance was measured in response to increasing concentrations of methacholine (Sigma-Aldrich, Buchs, Switzerland).
  • CD14 + monocytes and total T helper cells were isolated from human PBMCs using AutoMACS and reagents of Miltenyi Biotech (Bergisch
  • CD14 + monocytes were differentiated into monocyte derived dendritic cells (MDDC) in vitro with IL-4 and GM-CSF for 5 d.
  • Cells were stimulated with 1 mg/ml Neu5Gc (Inalcopharm, San Luis Obispo, USA).
  • Cytokines in supernatants were determined using Bioplex technology (BioRad, Hercules, USA).
  • RNA was isolated using the RNeasy plus mini kit of Qiagen (Hilden, Germany), cDNA was generated using enzymes of Fermentas (Schire, Germany), and gene expression was determined using Sybr green chemistry of BioRad.
  • T helper cells were stimulated in vitro with 1 mg/ml Neu5Gc for 5 days followed by a 2 days boost with anti-CD28, anti-CD3, and anti- CD2 antibodies. T helper cell differentiation was assessed by flow cytometry.
  • Tobit regression was used with anti-Neu5Gc IgG levels as the dependent variable.
  • Geometric means ratios (GMR) along with 95% confidence intervals (CI) were computed to describe the association between anti-Neu5Gc IgG levels and exposures.
  • Logistic regression was used to explore the association between binomial health outcomes and anti-Neu5Gc IgG and effects were expressed as odds ratios (OR) along with 95% CI.
  • anti-Neu5Gc IgG levels were introduced as a categorical variable (tertiles) to avoid data loss due to non-detection.

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Abstract

La présente invention concerne une méthode de prévention ou de traitement de maladies allergiques et inflammatoires, en particulier d'une maladie inflammatoire des voies respiratoires d'origine allergique, de l'asthme et/ou d'une allergie, comprenant l'administration de Neu5Gc. L'invention concerne en outre l'utilisation de Neu5Gc dans ladite prévention ou ledit traitement, et dans la fabrication de médicaments destinés à la prévention ou le traitement de maladies inflammatoires et allergiques, en particulier une maladie inflammatoire des voies respiratoires d'origine allergique, l'asthme et/ou une allergie.
PCT/EP2016/074108 2015-10-09 2016-10-07 Acide n-glycolyneuraminique pour la prévention ou le traitement de l'asthme ou de l'allergie WO2017060498A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
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US20050201952A1 (en) * 1998-01-29 2005-09-15 Yash Sharma Treatment and prevention of viral hepatitis infections
WO2006020210A1 (fr) * 2004-07-19 2006-02-23 Life Science Nutrition As Compositions de ngna et procédés d'utilisation de celles-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
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