• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    fucosylactose as a non-digestible oligosaccharide identical to breast milk with new functional benefit. the invention relates to nutritional compositions with fucosylactose for use in stimulating nk cells. the composition is suitable for children.
    公开号:BR112012000859B1
    申请号:R112012000859-5
    申请日:2010-07-12
    公开日:2021-08-03
    发明作者:Johan Garssen；Bernd Stahl；Alma Jildou Nauta；Eric Samain；Sophie Drouillard
    申请人:N.V. Nutricia；
    IPC主号:
    专利说明:

    field of invention
    [001] The present invention relates to infant nutrition with non-digestible oligosaccharides, and in particular their use to stimulate the immune system. Background of the invention
    [002] Human milk-fed infants have a lower incidence of infections, including viral infections, than formula-fed infants. Many components are thought to be in human milk, including immunoglobulins (such as IgA), interleukin (IL)-1, IL-6, IL-8, IL-10, interferon- (IFN-y), immunocompetent cells, growth factor of transformation^ (TGF-β), lactoferrin, nucleotides, and nondigestible oligosaccharides (NDO) are involved in protection against infection with enteric or respiratory pathogens. Dietary nucleotides and TGF-β were found to be competent and may be responsible for the increased activity of the natural killer cell.
    [003] NDO are the main constituent of human milk and are the main element of the innate immune system of human milk. Human NDO promote the growth of beneficial microbiota dominated by bifidobacteria and lactobacilli. Some human NDO are also known to be able to directly prevent the adhesion of pathogens and toxins.
    [004] Human milk is the preferred food for children. However, it is not always possible or desirable to breastfeed a child. In such cases infant formula or infant formula is a good alternative. These formulas must have an optimal composition to simulate the beneficial effects of breast milk as closely as possible.
    [005] WO 2007/067053 discloses infant formulas comprising prebiotics derived from plant inulin, galacturonic acid oligosaccharide and prebiotic transgalactooligosaccharide synthesized from lactose to GED - 5375049v1 reduce infections.
    [006] WO 2007/010084 discloses mannan-poly- and oligosaccharides for immune stimulation.
    [007] US 6,576,251 discloses a carbohydrate blend for enteral or parenterally administered dietary foods consisting of (a) monosaccharide(s), (b) oligosaccharide(s) (maximum hexasaccharides) and (c) polysaccharide(s) ) (at least heptasaccharides), where the mixing ratio a, b, c with respect to weight is: alpha = 1, b = 40 to 1000, and c = 1 to 50, and containing at least 1 percent by weight of freely occurring fucose and/or limited to an oligosaccharide and/or a polysaccharide. The carbohydrate blend is said to have both a nutritional and a biological effect that is considerably greater than the corresponding action of the individual constituents.
    [008] EP 1 629 850 provides a method and composition for the treatment and/or prevention of respiratory tract infection and/or respiratory tract infection disease, the method comprising orally administering a composition to a mammal, the composition comprising an indigestible oligosaccharide containing galactose and at least 5% by weight of digestible galactose saccharide.
    [009] EP 2 072 052 refers to a composition suitable for use in preventing opportunistic infections in immunocompromised individuals comprising a probiotic and a fucosylated oligosaccharide selected from the group comprising 2'-fucosylactose, 3'fucosylactose, diffucosylactose, lacto-N -fucopentaose, lacto-N-fucoexaose, fucosylact-N-hexaose and fucosylact-N-neoexaose. The document also reveals the use of such a composition in the prevention of opportunistic infections in immunocompromised individuals. Invention Summary
    [010] Human milk differs from the milk of domestic animals in that it has more NDO and that the NDO are structurally different. The human NDO group is very complex as it represents a heterogeneous group of over 130 different compounds with diverse sugar composition. Due to its complex and polymorphic structure, large-scale synthesis is complicated. Therefore it is not yet technically and economically feasible to prepare infant nutrition with an NDO composition identical to human milk.
    [011] Recently, new techniques have become available to chemically synthesize specific types of NDO identical to specific human NDO, thereby offering the opportunity to test the immunomodulatory capacity of specific human NDO in in vitro and in vivo assays.
    [012] The inventors unexpectedly found that fucosylactose (FL), an oligosaccharide abundantly present in human breast milk and with a relatively simple structure, specifically increases the number and thus the activity of natural killer (NK) cells. NK cells play an important role in the natural defense against viral infections and tumor cells. The discovery that a specific oligosaccharide is responsible for increasing NK cell activity now allows the design of nutritional compositions comprising FL, more particularly 2'-FL, for use to increase NK cell and/or NK cell activity. Detailed Description
    [013] The present invention thus relates to a method for stimulating NK cell activity and/or NK cell proliferation in an individual, the method comprising administering a composition comprising fucosylactose to the individual, the composition not being milk human. In one embodiment, the present method is a non-medical method of stimulating NK cell activity and/or NK cell proliferation in an individual. In one embodiment, the present method is for treating and/or preventing viral infections in an individual.
    [014] The present invention also relates to a method for treating and/or preventing viral infections in an individual, the method comprising administering a composition comprising fucosylactose to the individual, the composition not being human milk.
    [015] The invention can also be expressed as the use of fucosylactose in the manufacture of a composition to stimulate NK cell activity and/or NK cell proliferation, the composition not being human milk. In one embodiment, the composition is for treating and/or preventing viral infections.
    [016] The invention can also be expressed as the use of fucosylactose in the manufacture of a composition to treat and/or prevent viral infections, the composition not being human milk.
    [017] The invention can also be expressed as a composition comprising fucosylactose to stimulate, in particular for use in stimulating NK cell activity and/or NK cell proliferation, the composition not being human milk. In one embodiment, the composition is for use in treating and/or preventing viral infections.
    [018] The invention can also be expressed as a composition comprising fucosylactose to treat and/or prevent, in particular, for use in the treatment and/or prevention of viral infections, the composition not being human milk.
    [019] The invention also relates to a method for treating and/or preventing infections, by stimulating natural killer cell (NK) activity and/or NK cell proliferation, the method comprising administering a composition comprising fucosylactose to the individual, the composition not being human milk.
    [020] The invention can also be expressed as the use of fucosylactose in the manufacture of an enteral composition to treat and/or prevent infections, by stimulating the activity of the natural killer (NK) cell and/or proliferation of NK cells, the composition does not being human milk.
    [021] The invention can also be expressed as a composition comprising fucosylactose to treat and/or prevent infections, in particular for use in and/or to prevent infections, by stimulating natural killer cell (NK) activity and/or proliferation of NK cells, the composition not being human milk.
    [022] The invention also relates to a method of increasing the response to vaccination, the method comprising administering a composition comprising fucosylactose to the individual, the composition not being human milk. In one embodiment, the method is to increase the response to vaccination to vaccination with viral antigens.
    [023] The invention can also be expressed as the use of fucosylactose in the manufacture of an enteral composition to increase the response to vaccination. In one embodiment, the composition is for enhancing the vaccination response to vaccination with viral antigens.
    [024] The invention can also be expressed as a composition comprising fucosylactose to increase, in particular for use for increasing, the response to vaccination. In one embodiment, the composition is for enhancing the vaccination response to vaccination with viral antigens.
    [025] The composition which is administered according to the present method, or which is used according to the present invention, is preferably administered via the enteral route, more preferably via the oral route. Or in other words the composition is preferably for enteral, preferably oral administration or in other words the composition is an enteral composition, preferably oral. Fucosylactose
    [026] The present composition comprises fucosylactose. Fucosylactose (FL) is a non-digestible oligosaccharide present in human milk. It is not present in bovine milk. It consists of three units of monose, fucose, galactose and glucose linked together. Galactose bound to glucose through a beta 1->4 bond is called lactose. A fucose unit is linked to a galactose unit of a lactose via an alpha 1,2 bond (2'-fucosylactose, 2'-FL) or to the glucose unit via an alpha 1,3 (3-fucosylactose, 3-FL). The present composition preferably comprises 2'-FL.
    [027] 2'-FL, preferably α-L-Fuc(1->2)-β-D-Gal-(1->4)-D-Glc, and 3-FL, preferably α-L-Fuc- (1->3Hβ-D-Gal-(1->4)]-D-Glc), are commercially available, for example, from Sigma-Aldrich. Alternatively, they can be GED - 5375049v1 isolated from human milk, for example, as described in Andersson & Donald, 1981, J Chromatogr. 211:170-1744, or produced by genetically modified microorganisms, for example, as described in Albermann et al. 2001, Carbohydrate Res. 334:97-103.
    Preferably, a composition comprises 1 mg to 3 g of fucosylactose per 100 ml, more preferably 10 mg to 2 g, even more preferably 20 mg to 100 mg FL per 100 ml. On a dry weight basis, the composition preferably comprises 0.007% by weight to 20% by weight of fucosylactose, more preferably 0.07% by weight to 10% by weight even more preferably 0.15% by weight to 1% by weight. A lower amount of fucosylactose will be less effective in increasing NK cells and/or increasing NK cell activity, whereas too high an amount will result in unnecessary high costs for the product. Non-digestible oligosaccharides other than FL
    [029] The present invention preferably comprises non-digestible oligosaccharides (NDO) other than FL. Preferably NDO other than FL stimulate the growth of bifidobacteria and/or lactobacilli, more preferably bifidobacteria. An increased content of bifidobacteria and/or lactobacilli stimulates the formation of a healthy gut microbiota. NDO are preferably not or only partially digested in the intestine by the action of acids or digestive enzymes present in the human upper digestive tract, in particular in the small intestine and stomach, and are fermented by the human intestinal microbiota. For example, sucrose, lactose, maltose and common maltodextrins are considered digestible.
    [030] Preferably, the present composition comprises non-digestible oligosaccharides with a DP in the range of 2 to 250, more preferably 2 to 60. The non-digestible oligosaccharide is preferably at least one, more preferably at least two, preferably at least three selected from group consisting of fructo-oligosaccharides, galacto-oligosaccharides, xylo-oligosaccharides, arabino-oligosaccharides, arabinogalacto-oligosaccharides, gluco-oligosaccharides, chito-oligosaccharides, glucomano-oligosaccharides, galactomano-oligosaccharides, comprising sialo-oligosaccharides, comprising sialo-oligosaccharides, sialo-oligosaccharides, comprising sialo-oligosaccharides, sialo-oligosaccharides, comprising sialo-oligosaccharides uronic acid oligosaccharides. The fructo-oligosaccharides group includes inulins, the galactooligosaccharide group includes transgalactooligosaccharides or beta-galactooligosaccharides group, the glucooligosaccharide group includes cyclodextrins, gentio- and nigero-oligosaccharides and non-digestible polydextrose group -oligosaccharides includes partially hydrolyzed guar gum and uronic acid oligosaccharide group includes galacturonic acid oligosaccharides and pectin degradation products.
    [031] More preferably, the present invention comprises at least one, more preferably at least two, more preferably three selected from the group consisting of fructo-oligosaccharides, beta-galacto-oligosaccharides and uronic acid oligosaccharides. More preferably, the composition comprises beta-galactooligosaccharides.
    [032] In a preferred embodiment, the composition comprises a mixture of inulin and short-chain fructooligosaccharides. In a preferred embodiment, the composition comprises a mixture of galactooligosaccharides and fructooligosaccharides selected from the group consisting of short chain fructooligosaccharides and inulin, most preferably inulin. A mixture of at least two different non-digestible oligosaccharides advantageously stimulates the beneficial intestinal microbiota bacteria to a greater degree. Preferably, the weight ratio in a mixture of galacto-oligosaccharides and fructo-oligosaccharide is between 25 and 0.05, more preferably between 20 and 1. Galacto-oligosaccharides, preferably beta-galacto-oligosaccharides, are better able to stimulate bifidobacteria. Preferably the present composition comprises galactooligosaccharides, preferably beta-galactooligosaccharides, with a degree of polymerization (DP) of 2 to 10 and/or fructooligosaccharides with a DP of 2 to 60.
    [033] The galacto-oligosaccharides are preferably beta-galacto-oligosaccharides. In a particularly preferred embodiment, the present composition comprises betagalacto-oligosaccharides ([galactose]n-glucose; where n is an integer from 2 to 60, i.e., 2, 3, 4, 5, 6, ... 59 , 60; preferably n is selected from 2, 3, 4, 5, 6, 7, 8, 9 or 10), wherein the galactose units are mostly bonded together via a beta bond. Betagalactooligosaccharides are also referred to as transgalactooligosaccharides (TOS). Beta-galactooligosaccharides are, for example, sold under the trademark Vivinal™ (Borculo Domo Ingredients, Netherlands). Another suitable source is Bi2Munno (Classado). Preferably, the TOS comprise at least 80% beta-1,4 and beta-1.6 bonds based on total bonds, more preferably at least 90%.
    [034] Fructooligosaccharide is an NDO comprising a chain of beta-linked fructose units with an average DP or DP of 2 to 250, more preferably 2 to 100, even more preferably 10 to 60. Fructooligosaccharide includes inulin, levan and/or a mixed type of polyfructane. An especially preferred fructooligosaccharide is inulin. Suitable fructooligosaccharide for use in the compositions is also commercially available, for example Raftiline®HP (Orafti). Preferably, the fructooligosaccharide has an average DP above 20.
    [035] Uronic acid oligosaccharides are preferably obtained from pectin degradation products. Accordingly, the present composition preferably comprises a pectin degradation product with a DP between 2 and 100. Preferably, the pectin degradation product is prepared from apple pectin, beet pectin and/or citrus pectin. Preferably, the uronic acid oligosaccharide is a galacturonic acid oligosaccharide. Preferably, the composition comprises FL and one from the group selected from galactooligosaccharide and uronic acid oligosaccharide.
    [036] In addition to FL, more preferably the composition comprises beta-galacto-oligosaccharide, fructo-oligosaccharide and a uronic acid oligosaccharide. Such a combination has been found to act synergistically with fucosylactose, in particular 2-fucosylactose. The weight ratio of beta-galacto-oligosaccharide: fructo-oligosaccharide: uronic acid oligosaccharide is preferably (20 to 2):1:(1 to 20), more preferably (20 to 2):1:(1 to 10), further more preferably (20 to 2):1:(1 to 3), even more preferably (12 to 7):1:(1 to 2). More preferably the weight ratio is approximately 9:1:1.1. Preferably, the weight ratio of FL to beta-galacto-oligosaccharide, preferably TOS, is from 5 to 0.05, more preferably 5 to 0.1, most preferably from 2 to 0.1. Preferably, the weight ratio of FL to fructooligosaccharide, preferably inulin, is from 10 to 0.05, more preferably 10 to 0.1, more preferably from 2 to 0.5. Preferably the weight ratio of FL to uronic acid oligosaccharide, preferably pectin-derived, is from 10 to 0.05, more preferably 10 to 0.1, most preferably from 2 to 0.5.
    [037] Preferably, the composition comprises 80 mg to 4 g of non-digestible oligosaccharides, including fucosylactose per 100 ml, more preferably 150 mg to 2 mg, even more preferably 300 mg to 1 g of non-digestible oligosaccharides per 100 ml. On a dry weight basis, the composition preferably comprises 0.25% by weight to 25% by weight of non-digestible oligosaccharides including fucosylactose, more preferably 0.5% by weight to 10% by weight, even more preferably 1.5% by weight. weight to 7.5% by weight. A lower amount of non-digestible oligosaccharides will be less effective in stimulating beneficial bacteria in the microbiota, while too high an amount will result in side effects of abdominal bloating and discomfort. nutritional composition
    [038] Preferably the composition comprising fucosylactose is a nutritional composition. The composition of the present invention is non-human milk. The present composition is preferably enterally administered, more preferably orally.
    [039] The present composition is preferably a nutrition formula, preferably an infant formula. The present composition can be advantageously applied as a complete nutrition for children. The present composition preferably comprises a lipid component, protein component and carbohydrate component and is preferably administered in liquid form. The present invention includes dry food, preferably a powder which is accompanied with instructions how to mix the dry food mixture with a suitable liquid, preferably with water.
    [040] The present invention advantageously provides a composition in which the lipid component provides from 5 to 50% of the total calories, the protein component provides from 5 to 50% of the total calories, and the digestible carbohydrate component provides from 15 to 85% of total calories. The present invention advantageously provides a composition wherein the lipid component provides from 20 to 50% of the total calories, the protein component provides from 5 to 30% of the total calories, and the digestible carbohydrate component provides from 30 to 70 % of total calories. Preferably, in the present composition the lipid component provides from 35 to 50% of the total calories, the protein component provides from 7.5 to 12.5% of the total calories, and the digestible carbohydrate component provides from 40 to 55 % of total calories. By calculating the % of total calories for the protein component, the total energy provided by the proteins, peptides and amino acids needs to be taken into account.
    [041] The present composition preferably comprises at least one lipid selected from the group consisting of animal lipid, excluding human lipids, and vegetable lipids. Preferably, the present composition comprises a combination of vegetable lipids and at least one oil selected from the group consisting of fish oil, animal oil, seaweed oil, fungus oil, and bacterial oil. The present composition preferably comprises long chain polyunsaturated fatty acids (LC-PUFA). LC-PUFA are fatty acids or fatty acyl chains with a length of 20 to 24 carbon atoms, preferably 20 or 22 carbon atoms comprising two or more unsaturated bonds. More preferably the present composition comprises eicosapentaenoic acid (EPA, n-3), docosahexaenoic acid (DHA, n-3) and/or arachidonic acid (ARA, n-6).
    [042] Preferably, the present composition comprises at least 0.1% by weight, preferably at least 0.25% by weight, more preferably at least 0.6% by weight, even more preferably at least 0.75% by weight of LC-PUFA with 20 and 22 carbon atoms based on total fat content.
    [043] The content of LC-PUFA, particularly LC-PUFA with 20 and 22 carbon atoms, preferably does not exceed 6% by weight, more preferably does not exceed 3% by weight of the total fat content since it is desirable to simulate the human milk as much as possible. LC-PUFA can be supplied as free fatty acids, in triglyceride form, in diglyceride form, in monoglyceride form, in phospholipid form, or as a mixture of one or more of the above. The present composition preferably comprises between 5 and 75% by weight of polyunsaturated fatty acids based on total fat preferably between 10 and 50% by weight.
    [044] The protein used in the nutritional composition is preferably selected from the group consisting of non-human animal proteins (preferably milk proteins), vegetable proteins (preferably soy protein and/or rice protein), hydrolysates thereof, free amino acids and mixtures thereof. The present composition preferably contains casein, whey, hydrolyzed casein and/or hydrolyzed whey protein. Preferably the protein comprises intact proteins, more preferably intact bovine whey proteins and/or intact bovine casein proteins.
    [045] The present composition preferably contains digestible carbohydrates selected from the group consisting of sucrose, lactose, glucose, fructose, corn syrup solids, starch and maltodextrins, more preferably lactose.
    [046] In view of the above, it is also important that the liquid food does not have an excessive caloric density, yet still provide enough calories to feed the individual. Consequently, the liquid food preferably has a caloric density between 0.1 and 2.5 kcal/ml, even more preferably a caloric density between 0.5 and 1.5 kcal/ml, more preferably between 0.6 and 0.8 kcal/ml.
    [047] Preferably, the present composition comprises nucleotides and/or nucleosides, more preferably nucleotides. Preferably, the composition comprises cytidine 5'-monophosphate, uridine 5'-monophosphate, adenosine 5'-monophosphate, guanosine 5'-monophosphate, and/or inosine 5'-monophosphate, more preferably cytidine 5'-monophosphate, uridine 5'- monophosphate, adenosine 5'-monophosphate, guanosine 5'-monophosphate, and inosine 5'-monophosphate. Preferably, the composition comprises from 5 to 100, more preferably from 5 to 50 mg, more preferably from 10 to 50 mg of nucleotides and/or nucleosides per 100 gram dry weight of the composition. The presence of nucleotides and/or nucleosides advantageously stimulates NK cell activity. Nucleotides and/or nucleosides are intended to act synergistically with the fucosylactose of the present composition. Application
    [048] In one embodiment, the present composition is used to stimulate natural killer cell activity and/or natural killer cell proliferation. In one embodiment, the present invention is used to treat and/or prevent viral infections. In one embodiment, the composition for stimulating natural killer cell activity and/or natural killer cell proliferation, and/or for treating and/or preventing viral infections is for administering to HIV patients, elderly and/or cancer patients.
    [049] NK cells are a type of cytotoxic lymphocyte that constitutes a major component of the innate immune system. NK cells play a major role in defending against intracellular infections. NK cells are defined as large granular lymphocytes that do not express T cell antigen receptors (TCR) or CD3 Pan T marker or B cell receptor (Ig) of surface immunoglobulins, but normally express the surface markers CD16 (FcRIII) and CD56 in humans. They were termed “natural killers” because of the early notion that they do not require activation to kill cells that do not have “proper” class I major histocompatibility complex (MHC) markers. NK cells have two main types of effector function; cell killing and cytokine secretion. Increased NK cell activity (by increasing the number of NK cells and/or by increasing the specific activity of an NK cell) results in increased resistance against viral infections. The use of a nutritional composition comprising fucosylactose is therefore preferable to prevent and/or treat viral infections, more preferably viral infections caused by Ortomyxoviridae, in particular influenza virus, herpesviridae, rotavirus, cytomegalovirus, caliciviridae, respiratory syncytial virus, virus of human immunodeficiency and/or rhinovirus. The use of a nutritional composition comprising fucosylactose is therefore preferable to prevent and/or treat viral infections, more preferably the viral infections of the common cold, influenza, measles, chickenpox, viral diarrhea, viral gastroenteritis, HIV infection and/or viral infections of the respiratory tract. In a preferred embodiment, the present invention is used for patients with HIV. In one embodiment, the present invention relates to providing nutrition to a patient with HIV. The present composition is advantageous for HIV patients since HIV patients have a decreased natural killer cell activity.
    [050] The use of a nutritional composition comprising fucosylactose is therefore especially beneficial for infant formula. In one embodiment, the present invention relates to providing nutrition to a child. Formula-fed children have an underdeveloped immune system compared to adults and are more prone to viral infections than human milk-fed children. Preferably, the child is from 0 to 36 months of age, more preferably from 0 to 18 months, even more preferably from 0 to 12 months, most preferably from 0 to 6 months of age. The younger the child, the less developed the immune system.
    [051] The composition comprising fucosylactose is even more advantageously used in premature children and/or children with very low or low birth weight, since these children are even more vulnerable and/or prone to viral infections.
    [052] The composition comprising fucosylactose is even more advantageously used in children born by caesarean section. Children who are born by caesarean are born in a hospital in an environment with more pathogens against which antibodies, given by the mother to the baby, are not effective. Children born by cesarean have a delayed and less than optimal colonization of the large intestinal tract and are therefore also more prone to intestinal infections.
    [053] The composition comprising fucosylactose is advantageously used for elderly nutrition. In one embodiment, the present invention relates to providing nutrition to an elderly person. An elderly person is a person aged 55 or over, in particular 65 or over. Elderly people have demonstrated less activity of natural killer cell activity than healthy young adult individuals. Elderly people are especially vulnerable to complications from viral infection. In a preferred embodiment, the present invention is used for treating and/or preventing immunosenescence in the elderly. Elderly people are more likely to develop tumors. NK cell activity suppresses tumor cell proliferation. In a preferred embodiment, the present invention is used for nutrition in cancer patients. Oncology patients have lower natural killer cell activity than healthy young adult individuals.ExamplesExample 1:
    [054] Materials and methods:
    [055] 6-8 week old female C57BL/6 mice (Charles River) received semi-purified AIN-93G based diets (Research Diet Service, Wijk bij Duurstede, Netherlands), comprising 1.) 2% by weight of beta-galacto-oligosaccharide (GOS, source VivinalGOS, Borculo Domo), fructooligosaccharide (FOS, source RaftilineHP, Orafti) and galacturonic acid oligosaccharide (source AOS) in a ratio of 9:1:1.1. AOS are produced from pectin (Sudzucker AG, Mannheim, Germany) with a DP of 1-20. It consists of approximately 75% galacturonic acid oligomers, based on total weight,2 .) 1% by weight lactoneotetraose (LNnT),3 .) 1% by weight 3'-sialyl-lactose (3'-SL ), or 4.) 1% by weight of 2'-fucosylactose (2'-FL).
    [056] All groups were compared to the non-supplemented control diet. Dietary supplementation started 14 days before the first vaccination and lasted until the end of the experiment, 31 days after the first vaccination.
    [057] Vaccination experiments were carried out using Influvac (Solvay Pharmacheuticals, Weesp, Netherlands) from the period 2005/2006. The mice received a primary vaccination and a booster vaccination, consisting of a subcutaneous (sc) injection of a 1:1 mixture of vaccine and adjuvant in a total volume of 100 μl. Booster vaccination was given 21 days after the primary vaccination. The experiments ended 10 days after the booster vaccination. Blood samples were taken at the end of the experiment. Negative control groups that were included received injections with a 1:1 mixture of PBS and adjuvant in a total volume of 100 µl. To determine the percentage of NK cells, cells were labeled with FITC-labeled anti-mouse CD3 mAb in combination with PE-labeled anti-mouse NK1.1 mAb. NK cell cytotoxicity in spleen cell suspensions was assayed using standard 51Cr release assays. NK cell cytotoxicity was tested using YAC-1 target cells. The percent specific 51Cr release was calculated as the percent specific lysis = (experimental release - spontaneous release)/(total detergent release - spontaneous release) x 100. Spontaneous release values were always <15% total lysis.
    [058] The percentage of regulatory T cells (Treg) was determined by flow cytometry (FACSCalibur) using anti-mouse CD3 mAb labeled with allophycocyanin (APC), anti-mouse CD4 mAb labeled with Pe-Cy5 and anti-mouse CD25 mAb labeled with phycoerythrin (PE) in combination with intracellular staining of Foxp3 mAb labeled with isothiocyanate-fluorescein (FITC) according to the instructions offered by the manufacturers (eBiosciences, San Diego, CA).
    [059] Statistical analysis was performed using GraphPadPrism software. Statistical differences between control and test groups were analyzed by ANOVA and Dunnett's post hoc test if multiple groups were compared with a single group (control). P values < 0.05 were considered significant in all experiments.
    [060] The immunomodulatory effect of three chemically synthesized human oligosaccharides was compared with GOS/FOS/AOS. Supplementation with GOS/FOS/AOS, LNnT, 2’-FL or 3’-SL resulted in a significant increase in the DTH response, a TH1-dependent parameter, compared to the control fed animals.
    [061] Interestingly, the percentage of NK cells in the spleen was significantly increased in mice supplemented with human oligosaccharides compared to mice supplemented with GOS/FOS/AOS and control, see table 1. This effect was higher at 2' -FL. To examine whether the increase in the percentage of NK cells in groups supplemented with human oligosaccharides also correlated with functional activity, NK cell activity was measured in mouse splenocytes. Significantly increased NK cell activity was detected in splenocytes from mice that were supplemented with 2'-FL compared to controls, see table 1.Table 1: Effect of human milk NDO-like NDO on NK cell activity and NK cells
    * Indicates p<0.05 compared to the control group** indicates p<0.01 compared to the control group
    [062] Finally, the amount of regulatory T cells (Treg) was decreased to the highest point with the FL diet as seen in Table 2. regulatory T cells Treg.
    * Indicates p < 0.05 compared to the control group
    [063] The decrease in regulatory T cells is indicative of a decreased inhibition of the immune response and consequently allows for an increased vaccination response to viral antigens. A temporary decrease in regulatory T cells can be especially beneficial when vaccination is to take place.
    [064] Overall, these results support that oral supplementation with 2’-FL stimulates NK cell growth and/or activity. These results are indicative of an effect of dietary 2’-FL to enhance the response to vaccination, in particular vaccination with viral antigens. These results are indicative of an effect of 2’-FL of diet to treat and/or prevent viral infections.Example 2
    [065] Infant formula to stimulate NK cell activity comprising per 100 ml (13.9 dry weight): 1.4 g protein (whey and casein) 7.3 g digestible carbohydrates (including lactose)3 .6 g of fat (vegetable fat, fish oil) 0.8 g of non-digestible oligosaccharides of which 80 mg 2'-fucosylactose and 640 mg of beta-galacto-oligosaccharides, and 80 mg of fructo-oligosaccharides
    [066] Additionally included are: choline, myoinositol, taurine, minerals, trace elements, and vitamins as known in the art.Example 3
    [067] A preferred composition that can be used for the stimulation of natural killer cell activity in HIV patients may comprise per 100 g dry weight.Dietary fiber 5-50 gFructo-oligosaccharide Galacto-oligosaccharide Pectin hydrolyzate 2'- FL 5% total dietary fiber 40% total dietary fiber 50% total dietary fiber5% total dietary fiber N-acetyl cysteine 0.5 - 5 gCarbohydrate (not dietary fiber) 2-20 gFat 4-20 g
    权利要求:
    Claims (7)
    [0001]
    1. USE OF 2’-FUCOSYLACTOSIS, characterized by being in the manufacture of an enteral composition to increase the response to vaccination with a viral antigen and in which the composition is not human milk.
    [0002]
    2. USE, according to claim 1, characterized in that the composition is to be administered to children, patients with HIV, the elderly and/or oncology patients.
    [0003]
    3. USE, according to claim 2, characterized in that it is to provide nutrition to a child.
    [0004]
    4. USE, according to claim 2, characterized in that it is to provide nutrition to a patient with HIV, an elderly person and/or an oncology patient.
    [0005]
    5. USE, according to any one of claims 1 to 4, characterized by the fact that the composition additionally comprises at least one selected from the group consisting of beta-galactooligosaccharides, fructooligosaccharides and uronic acid oligosaccharides.
    [0006]
    6. USE, according to any one of claims 1 to 5, characterized in that the composition comprises 0.07 to 1% by weight of fucosylactose based on the dry weight of the composition.
    [0007]
    7. USE, according to any one of claims 1 to 6, characterized by the fact that the composition comprises 5 to 50% protein, 15 to 85% digestible carbohydrates and 5 to 50% fat based on total energy.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US5002759A|1989-07-25|1991-03-26|Colgate-Palmolive Company|Oligosaccharide inhibition of Streptococcus pyogenes adhesion|
    US6204431B1|1994-03-09|2001-03-20|Abbott Laboratories|Transgenic non-human mammals expressing heterologous glycosyltransferase DNA sequences produce oligosaccharides and glycoproteins in their milk|
    DE19701382A1|1997-01-16|1998-07-23|Nutricia Nv|Carbohydrate mix|
    US20020019991A1|1998-04-30|2002-02-14|Abbott Laboratories|Compositions containing an alpha 1,2-fucose linkage and uses thereof|
    DE19836339B4|1998-08-11|2011-12-22|N.V. Nutricia|carbohydrate mix|
    HU0204546A3|2000-03-01|2003-10-28|Nestle Sa|Carbohydrate formulation for enhancement of immune response|
    FR2814471B1|2000-09-27|2004-12-17|Centre Nat Rech Scient|USE OF XYLOGLUCANE POLYMERS AND OLIGOMERS, AND DERIVATIVE COMPOUNDS, AS PHYTOSANITARY AND BIOFERTILIZING PRODUCTS|
    DE602004017885D1|2003-10-24|2009-01-02|Nutricia Nv|SYMBIOTIC COMPOSITION FOR SMALL CHILDREN|
    EP1721612B1|2003-10-24|2009-04-22|N.V. Nutricia|Immunemodulating oligosaccharides|
    EP2497478A3|2003-12-05|2012-11-07|Children's Hospital Medical Center|Oligosaccaride compositions and use thereof in the treatment of infection|
    EP1597978A1|2004-05-17|2005-11-23|Nutricia N.V.|Synergism of GOS and polyfructose|
    DK1629850T4|2004-08-24|2013-07-01|Nutricia Nv|Nutritional composition containing indigestible oligosaccharides|
    AU2006215603A1|2005-02-21|2006-08-24|Nestec S.A.|Oligosaccharide mixture|
    WO2007010084A2|2005-07-15|2007-01-25|Johannes Savolainen|Immunostimulatory oligo- and polysaccharides and uses thereof|
    EP1776877A1|2005-10-21|2007-04-25|N.V. Nutricia|Method for stimulating the intestinal flora|
    US20090156550A1|2005-12-06|2009-06-18|Potappel-Van T Land Belinda|Composition containing oligosaccharides for the treatment/prevention of infections|
    CA2645472C|2006-03-10|2015-09-15|N.V. Nutricia|Use of non-digestable saccharides for giving an infant the best start after birth|
    WO2007114683A1|2006-03-30|2007-10-11|N.V. Nutricia|Milk oligosaccharides for stimulating the immune system|
    US9239329B2|2006-12-18|2016-01-19|Japan Science And Technology Agency|Method of measuring interaction between biomaterial and sugar chain, method of evaluating biomaterial in sugar chain selectivity, method of screening biomaterial, method of patterning biomaterials, and kits for performing these methods|
    WO2009067000A1|2007-11-20|2009-05-28|N.V. Nutricia|Composition with synbiotics|
    EP2072052A1|2007-12-17|2009-06-24|Nestec S.A.|Prevention of opportunistic infections in immune-compromised subjects|
    WO2010143940A1|2009-06-12|2010-12-16|N.V. Nutricia|Synergistic mixture of beta-galacto-oligosaccharides with beta-1,3 and beta-1,4/1,6 linkages|
    MY164674A|2009-07-15|2018-01-30|Nutricia Nv|Fucosyllactose as breast milk identical non-digestible oligosaccharide with new functional benefit|
    CN106890329A|2009-07-15|2017-06-27|N·V·努特里奇亚|For the mixture of the indigestible oligosaccharide of stimulating immune system|
    EP2658546B1|2010-12-31|2018-12-05|Abbott Laboratories|Methods of using human milk oligosaccharides for improving airway respiratory health|
    WO2015071391A1|2013-11-15|2015-05-21|Nestec S.A.|Infant formulas containing a 2-fucosylated oligosaccharide for treatment or prevention of influenza infection|
    US20160316808A1|2013-12-12|2016-11-03|Nestec S.A.|Synthetic nutritional compositions especially adapted for male and female infants and young children|MY164674A|2009-07-15|2018-01-30|Nutricia Nv|Fucosyllactose as breast milk identical non-digestible oligosaccharide with new functional benefit|
    CN106890329A|2009-07-15|2017-06-27|N·V·努特里奇亚|For the mixture of the indigestible oligosaccharide of stimulating immune system|
    EP2465509A1|2010-11-23|2012-06-20|Nestec S.A.|Oligosaccharide composition for treating acute respiratory tract infections|
    BR112013016903A2|2010-12-31|2019-09-24|Abbott Lab|human milk oligosaccharides to modulate inflammation|
    EP2658400A2|2010-12-31|2013-11-06|Abbott Laboratories|Nutritional formulations including human milk oligosaccharides and antioxidants and uses thereof|
    NZ612472A|2010-12-31|2015-02-27|Abbott Lab|Nutritional compositions comprising human milk oligosaccharides and nucleotides and uses thereof for treating and/or preventing enteric viral infection|
    SG191394A1|2010-12-31|2013-08-30|Abbott Lab|Methods for reducing the incidence of oxidative stress using human milk oligosaccharides, vitamin c and anti-inflammatory agents|
    EP2658546B1|2010-12-31|2018-12-05|Abbott Laboratories|Methods of using human milk oligosaccharides for improving airway respiratory health|
    SG10202110501RA|2010-12-31|2021-11-29|Abbott Lab|Methods For Decreasing The Incidence Of Necrotizing Enterocolitis In Infants, Toddlers, Or Children Using Human Milk Oligosaccharides|
    WO2012158517A1|2011-05-13|2012-11-22|Glycosyn LLC|The use of purified 2'-fucosyllactose, 3-fucosyllactose and lactodifucotetraose as prebiotics|
    WO2013032674A1|2011-08-29|2013-03-07|Abbott Laboratories|Human milk oligosaccharides for preventing injury and/or promoting healing of the gastrointestinal tract|
    EP2830712A1|2012-03-27|2015-02-04|Abbott Laboratories|Methods for modulating cell-mediated immunity using human milk oligosaccharides|
    EP2656862A1|2012-04-24|2013-10-30|The Procter & Gamble Company|Substrate comprising one or more human milk oligosaccharides and disposable absorbent article comprising the substrate|
    DK2708145T3|2012-09-14|2016-07-18|Abbott Lab|Nutritional Compositions for Use in Methods to Modulate Corticosterone Levels in Psychologically Stressed Individuals|
    WO2015071391A1|2013-11-15|2015-05-21|Nestec S.A.|Infant formulas containing a 2-fucosylated oligosaccharide for treatment or prevention of influenza infection|
    US10568896B2|2013-11-19|2020-02-25|Abbott Laboratories|Methods for preventing or mitigating acute allergic responses using human milk oligosaccharides|
    CN113331426A|2014-04-08|2021-09-03|雅培公司|Methods of using human milk oligosaccharides to enhance mucosal innate immune responses and/or detection to pathogens|
    CN107405354A|2015-03-05|2017-11-28|格礼卡姆股份公司|Treat the composition and method of ARI|
    RU2720201C2|2015-03-05|2020-04-27|Сосьете Де Продюи Нестле С.А.|Compositions for use in the prevention or treatment of otitis media or bronchitis in infants or young children|
    EP3298404A1|2015-05-19|2018-03-28|Nestec S.A.|Kit-of-parts to identify mother's milk missing fucosyltransferase-2 dependent glycans and feeding doses with said glycans|
    CN104940925A|2015-07-17|2015-09-30|宁波荣安生物药业有限公司|Rabies vaccine for human use and preparation method of rabies vaccine|
    RU2742510C2|2016-09-07|2021-02-08|Сосьете Де Продюи Нестле С.А.|Nutritional composition for infants and/or young children containing oligosaccharides|
    WO2019031961A1|2017-08-11|2019-02-14|N.V. Nutricia|Human milk oligosaccharide for improving immune fitness|
    CN107373674A|2017-08-25|2017-11-24|西宝生物科技（上海）股份有限公司|Alimentation composition and its application after a kind of oncotherapy|
    AU2018431641A1|2018-07-12|2021-01-21|N.V. Nutricia|Nutritional composition for use in the treatment of diarrhea, its preparation and method of treatment|
    WO2020243371A1|2019-05-28|2020-12-03|Massachusetts Institute Of Technology|Methods and compositions for modulating immune responses|
    CN114072013A|2019-05-29|2022-02-18|N·V·努特里奇亚|Non-digestible oligosaccharides for reducing colonic protein fermentation|
    EP3888661A1|2020-03-31|2021-10-06|FrieslandCampina Nederland B.V.|Compositions comprising 2 -fucosyllactose to prevent viral infections|
    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-10-15| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-10-06| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-10-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-01-19| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-01-26| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-02-02| B07B| Technical examination (opinion): publication cancelled [chapter 7.2 patent gazette]|
    2021-05-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-08-03| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 12/07/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP09165485|2009-07-15|
    NL09165485.5|2009-07-15|
    EP09165485.5|2009-07-15|
    US25645309P| true| 2009-10-30|2009-10-30|
    US61/256,453|2009-10-30|
    PCT/NL2010/050447|WO2011008087A1|2009-07-15|2010-07-12|Fucosyllactose as breast milk identical non-digestible oligosaccharide with new functional benefit|BR122021007429-1A| BR122021007429B1|2009-07-15|2010-07-12|USE OF 2'-FUCOSYLACTOSIS IN THE MANUFACTURING OF AN ENTERAL COMPOSITION|
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