TW201247111A - Lactobacillus paracasei NCC2461 (ST11) for use by perinatal maternal administration in the reduction and prevention of allergies in progeny - Google Patents

Abstract

The present invention provides a probiotic, Lactobacillus paracasei NCC 2461, i.e. ST11, for use by administration to expectant females and/or lactating mothers, and to their progeny for the reduction or prevention of the development of allergic immune responses in progeny. A daily dose of ST11 is administered to a pregnant woman for at least two weeks before delivery and, after delivery, the daily dose of ST11, is administered to the lactating mother or the newborn infant for at least two months, either directly or via the mother's milk. The infant immune responses to allergens are thus reduced, resulting in a ''dampened'' allergic response. Thus allergy, including atopy, may be prevented in the progeny.

Description

201247111 VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention relates to probiotics capable of regulating an immune response to an allergen in an infant during a near-term period. [Prior Art] The incidence of allergic diseases has risen rapidly in recent decades. Since more than one-half of the world's population suffers from allergies to date, it has been considered a new epidemic in industrialized countries. The reasons for the steady increase in allergic diseases have not been fully understood. The genetic background of the host is the main factor, and recently discovered genes have been shown to be associated with respiratory allergy/asthma and skin symptoms [H〇u〇way, JW et al., (2010); Genetics 〇f Allergic Disease, " c / , 125: S81-94]. Environmental factors such as lifestyle, HIV infection, reduced family size, and reduced health stimulation of the immune system in the early stages of life appear to play an important role. Allergic sensitization in childhood, especially in early childhood and especially for food allergens, is critical and most interesting because it has been shown that the occurrence of "allergic phenotypes" or "ectopic reactions" promotes subsequent harm to other allergens. reaction. Therefore, childhood allergies may be the first step in an allergic cascade that produces multiple allergies in later life (commonly referred to as the "Atopic March"). For example, children who continue to have food allergies in early life in the human group have been shown to have a significantly increased risk of developing allergic rhinitis (hay fever) or asthma later in childhood (0stb1〇m, E. et al., 2008 Phen〇types 〇ff〇〇d and development of allergic diseases during the first 8 163796.doc 201247111 years of life, Clinical and Experimental Allergy, 38 (8): 1325-1332). Therefore, preventing food allergies from attacking or attenuating their severity may be especially important for slowing down the allergic reaction. In this regard, the management of allergic events in childhood and infancy and the prevention of allergies are the most important. Prevention of allergies can be achieved to varying degrees: "Primary prevention" is the effect of preventing or reducing the risk of sensitization of a patient to an allergen, characterized by the absence of allergen-specific IgE antibodies or their reduced levels. Preventing or reducing sensitization will result in no allergic symptoms or reduced symptoms when re-exposed to the same allergen. The present invention relates to the prevention of allergies. "Secondary prevention" is the regulation of allergic symptoms (ie, allergic reactions to a patient who has been allergic to one or several allergens when the patient is re-exposed to the (or other) allergen or The effect of strength). By regulating the occurrence or intensity of allergic symptoms (secondary prevention), the negative effects of allergies related to the quality of life of allergic patients are minimized. In the presence of these different allergy prevention concepts, it is hypothesized that by virtue of their inherent mechanism of action, some compounds may act on only one or both of these particular levels of prevention. Some may only reduce, for example, the risk of sensitization of a particular allergen (-level prophylaxis), while other compounds may only act on secondary prevention and reduce the severity of the allergic response. Other compounds can affect sensitization and symptoms and are therefore effective in promoting primary and secondary prevention. Food allergens are among the first allergens that infants encounter in their early life. - Infants who have not received exclusive breastfeeding are usually exposed to milk. 163796.doc 201247111 Protein. Milk white is actually one of the most commonly observed causes of food allergies in infancy, followed by eggs and wheat eggs. In general, food allergies can manifest as skin symptoms (skin treatment, moist treatment, other symptoms) and gastrointestinal symptoms (abdominal 痉m, especially abdominal pain ^ vomiting) in infants and young children. Other sensitization and allergic events can also occur when infants/children are exposed to new foods such as cereals, vegetables, fruits, nuts or fish, and airborne allergens such as pollen. Airborne allergens such as pollen, indoor dust worms and animal dander are also the main causes of allergies in children and adults. It is known that birch pollen allergies usually exhibit allergic symptoms after ingesting several types of plant-derived foods [Vieths, S., Scheurer, S. and Ballmer-Weber, B. (2002);

Current Understanding of Cross-Reactivity of Food Allergens and Pollen, Annals of the New York Academy of Sciences, 964; 47-68.]. Most of these reactions are caused by four different parent-reactive protein structures present in birch pollen. The proteins that share the epitope with β and Bet v 1 (ie, the main birch b powder allergen) are present in several species. Pollen and fruits and vegetables such as apples, stone fruits, celery, carrots, nuts and soybeans. In the Vieths 4 study, approximately 70% of the patients studied for allergies to the tree pollen experienced symptoms after consuming food from these groups. Therefore, the occurrence of allergies to airborne allergens such as birch pollen is also directly related to food allergy manifestation, which is called cross-reactivity in oral syndrome. Gastrointestinal microbial phase and immune system Symbiotic gastrointestinal microbes for the development of intestinal-associated lymphoid tissue and related immune systems 163796.doc 201247111 The earliest and most substantial stimulation. Reliable evidence from epidemiological studies has shown that, for example, reduced consumption of fermented foods, extensive use of antibiotics and other drugs, and improved Western-style living conditions are associated with increased allergic diseases. The so-called “hygiene hypothesis” suggests that the lack of exposure to microbial stimuli in early childhood is a major factor associated with this trend [Von Mutius, E. (2007); Allergies, Infections and the hygiene hypothesis - The epidemiological evidence, 212 (6 433-9] 〇 In fact, epidemiological studies have demonstrated a link between the development of allergic diseases and gastrointestinal microbial disorders. For example, it has been reported that in Western society, lactobacilli or bifidobacteria are usually absent in children with atopic constitution compared to healthy children [Suzuki, S., Shimojo, N., Tajiri, Y., Kumemura , M., Kohno, Y. (2007); Differences in the composition of intestinal Bifidobacterium species and the development of allergic diseases in infants in rural Japan, Clin Exp Allergy; 37; 506-511; Ouwehand, AC, Isolauri, E. , He, F., Hashimoto, H., Benno, Y., Salminen, S. (2001); Differences in Bifidobacterium flora composition in allergic and healthy infants, J. Allergy Clin. Immunol. 108; 144-145; Kalliomaki, M., Salminen, S., Arivilommi, H., Kero, P., Koskinen, P. and Isolauri, E. (2001); Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial, Zawcei 357: 1076 -9] o Interestingly, in response to infant feeding, the composition of the intestinal microbial phase is clearly defined as 163796.doc 201247111. The fecal microbial phase of breast-fed infants includes considerable Bifidobacterium populations and some Lactobacillus species, while formula-fed infants have more complex microbial phases, with Bifidobacterium species and Bacteroides (10,000). In order to turn (7) "species", there are usually also clostridia and streptococci. After weaning, an intestinal microbial phase pattern similar to the adult model is established over time [Penders, J (2006); Gut microbiota composition and development of atopic manifestations in infancy: the KOALA birth cohort study.

Gut 56: 661-667] ° The results of these studies provide a rational treatment for the prevention of allergic diseases by supplementing human diets with probiotics. In addition, as is known, the frequency and/or severity of allergies in breast-fed children is lower than that of formula-fed children, thus supporting probiotic interventions that promote intestinal microflora in non-breastfeeding children. Breastfeeding children are as similar as possible. There is also evidence that immunization programmes through environmental factors can function within a narrow window of opportunity, ie during pregnancy or early childhood when the immune response is still developing [Aaltonen, J., Ojala, T., Laitinen, K., Poussa, T.} Ozanne, S., Isolauri, E. (2011); Impact of maternal diet during pregnancy and breastfeeding on infant metabolic programming: a prospective randomized controlled study. E. Ewr. «/. C7i«. iVwir. 65; 10 -19] o Therefore, the immune status of the newborn is very important. This condition includes the protection that exists when the baby is born and is acquired during the first few hours of the baby's life, during the first few days of 163796.doc 201247111 or during the first few weeks. The ability to acquire and maintain this protection is a key factor in the health of the baby in the face of the new environment. Thus, prenatal, near-producing, and/or postpartum intervention is equivalent to a reliable method of modulating an immune response to promote and/or maintain a non-ectopic state. In addition, pregnancy/lactation interventions can have considerable advantages in terms of convenience and compliance compared to childhood-directed interventions. However, recent reports have confirmed that probiotic and/or postpartum probiotic treatments do not produce predictable results. For example, WO 01/97822 discloses that Lactobacillus rhamnosus GGaaciofeacz'/Zw·?r/zam/iojwi GG) is administered from 2 to 4 weeks before splitting and during maternal feeding or from birth 6 In the case of children who are directly given to children at high risk, the incidence of eczema is reduced by about 50% at 2 years of age. However, in the paper from κ〇ρρ et al. (2008), the same strain reported controversial results [Κορρ et al, (2〇〇8); Randomized, Double Blind, Placebo Controlled Trial of probiotics for Primary Prevention: No Clinical effects of

Lactobacillus GG supplementation, Vol. 121, No. 4]. The administration of Lactobacillus rhamnosus gg to the mother 4 to 6 weeks before the expected split and subsequent administration of the offspring within 6 months does not reduce the incidence of atopic dermatitis and does not change the affected children. The severity of atopic dermatitis. The conclusion of this paper is that Lactobacillus rhamnosus GG is generally not recommended for primary prevention. These experimental lines are performed on specific subgroups of the general population, that is, offspring with high allergic risk. It is disclosed in WO 2009/118243 that direct administration of progeny specific probiotic microorganisms after administration of female small gestation or lactation 163796.doc 201247111 enhances progeny immunity. Therefore, administration of Lactobacillus rhamnosus CGMCC 1.3724 (LPR) increased the peripheral IgG response of mouse pups to measles vaccine. However, this effect is specific to the strain used. Therefore, according to the prior art documents cited herein, further developments are needed in the field of administering probiotics as a means of improving the health of newborn babies and infants. Therefore, it is necessary to positively influence the health status of the offspring by the target nutritious diet of the mother to be produced, and in particular to act on the offspring. The need to prevent allergies or reduce the risk of allergies early in the life of the offspring to promote the health of the offspring. The details of 'the need to help ensure the best immune system in the offspring, so that the offspring to best prepare for early life antigen challenge, and enhance the future maturity of their immune system to better promote the subsequent infancy Protection. It is necessary to influence the construction of the immune system of the offspring at the earliest possible stage during pregnancy and during the early life of the newborn. SUMMARY OF THE INVENTION The present invention provides a probiotic Lactobacillus paracasei NCC 2461, i.e., ST11' for administration of a female and/or lactating mother and her progeny to reduce or prevent allergic immune responses in the offspring. The allergic immune response is reduced relative to the progeny of the mother who is not treated with ST11. The offspring can be offspring with a risk of ectopic disease. The allergic immune response to which the present invention is directed is directed to food or airborne allergens, particularly birch pollen allergens Bet v 1 and Bet v 2 . The allergic immune response can be allergen-specific I63796.doc •10- 201247111 Sexual recall response or non-allergen-specific (mitogen) induction response. A reduction in allergic immune response may be manifested by a decrease in IL-4 and IL-5 production in the case of an allergen-specific recall response, and/or as a result of a mitogen-induced response by L-5 produced by a committed lymphocyte. cut back. As a result, the infant's immune response to allergens is reduced, resulting in an allergic reaction in the offspring. Therefore, allergies can be prevented in the progeny, including according to the present invention, ST11 is administered to the mother to be produced for at least two weeks before delivery, and the offspring are administered directly or via the mother's milk for at least 2 months after delivery, preferably after delivery. Up to 6 months or even up to 1 year. Thus, the mother receives STi丨 at a dose of sputum at least part or all of her gestation period and at least part or all of her lactation (if she is breast-fed) after delivery. sTl 1 may be administered orally or to a lactating mother in the form of food, drink, food supplement or pharmaceutical composition. The daily dose of sputum is administered to the newborn infant directly or via the mother's milk for at least two months, preferably up to six months. It can be administered neat or diluted with water, breast milk or infant formula.

曰 dose is lxio6 to lxl〇H

Cfu (cfu is a community forming unit). Investing in the ST11 of the expectant or lactating mother

_ split front to surname pregnant women to give daily doses of Lactobacillus paracasei I63796.doc -11- 201247111 NCC 2461 (ST11) for at least two weeks, and - after childbirth, to give daily doses to newborn babies Probiotics for at least 6 months are better than 6 months or 1 year after delivery. [Embodiment] Definition: In this specification, the following terms have the following meanings: "Wilding period" is the adaptation of infants from pure liquid nutrients to solid or semi-solid foods and by almost exclusively food type (generally parent milk or infant formula). Milk) Adapted to a variety of food periods. "Allergenic" means the induction/production of an allergen-specific IgE antibody. "Non-allergen-specific immune response" means the production of cytokines by non-specifically stimulating immune cells by concanavalin A (Con A), which is a mitogen-stimulated lymphocyte. That is, committed T cells. Therefore, the term "non-allergen-specific immune response" is synonymous with "mitogen-induced immune response". "Probiotics" means microbial cell preparations or microbial cell components that have a beneficial effect on the health or well-being of the host. (Salminen s,

Ouwehand A. Benno Y. et al., “pr〇biotics: how should they be defined” Food Tec/iwo/. (1999): 10 107-1〇) 定义 The definition of probiotics is generally considered to be consistent with the WHO definition. The probiotic may comprise a unique microbial strain, a mixture of various strains and/or a mixture of various bacterial species and bacterial species. In the case of a mixture, the singular term "probiotic" can still be used to mean a probiotic mixture or a probiotic preparation. For the purposes of the present invention, microorganisms of the genus Lactobacillus are considered to be probiotics. 163796.doc 12 201247111 Beneficial probiotics generally means an indigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of the microorganisms present in the gut of the host and thus attempts to improve the health of the host. The Lactobacillus strain Ncc 2461 (Nestle Culture collection) is an alternative name used in this article, and the international identification reference code is CNCM 1-2116 (the country of the Pasteur Institute) Lactobacillus paracasei from the Culture and Microorganisms Collection (C〇1Iecti〇n Nationaie de Cultures de Microorganismes at Institute Pasteur), Paris, France). (:1^(:]^Identification code refers to the National Culture and Microbial Depository of the Pasteur Institute, 22 rue du d〇cte

Roux,75724 Paris, France 〇«The risk of allergies and/or atopic diseases means an individual (a family history of positive allergies in the heart) where at least one first-degree relative parent or compatriot has a publicly recognized allergic disease, such as an ectopic Sexual eczema, asthma, hay fever or food allergy' or individual (8) exhibit at least one allergy event such as atopic, asthma, hay fever or food allergy. This definition is associated with, for example, the use of allergic risks in scientific publications. The general definition of infants is consistent, such as j. AUergyCHn. Immunol, Vol. 121, No. 6, page 6, Berg et al., p. 1443, "Subjects". The present invention provides a probiotic iST11 for use in the production of The parent and its progeny are intended to reduce or prevent allergic immune responses in the offspring. Accordingly, the present invention provides a method of preventing or reducing allergies in an infant. All infants may benefit from the present invention 'including due to their family history. Infants at risk of developing an atopic disease. 163796.doc • 13- 201247111 According to the present invention, ST11 is administered to pregnant women for at least two weeks prior to delivery. 'And after the delivery, the daily dose of ST11 is administered to the newborn infant directly or via the mother's milk for at least two months. Accordingly, the present invention is also directed to a composition comprising ST1 i for use in accordance with the protocol as described above Inhibiting an allergic immune response with the parent and its progeny, reducing or preventing progeny, by administering ST11 of the present invention, advantageously affects the intestinal microbial phase of the infant. By administering ST11 to the mother during pregnancy and after delivery Infants are given ST11, and the immune response to allergens is reduced, so the allergic reaction is “weakened” and allergies including atopic reactions can be prevented. This effect is elaborated in the following paragraphs. Probiotic dose: Investing Or the dose of ST11 for breastfeeding mother is lxi〇6 to lxio" cfu, preferably lxl〇8 to lxl〇iQ cfu (cfu is a colony forming unit). The dose for neonatal infants is 1><1〇 2 to lxl〇1〇, preferably in the range of lxlO2 to lxl〇4 cfu. Therefore, the percentage of ST11 in the composition can be in a wide range, with the restriction that it delivers the immunoprotective effect. Preferably, the amount of ST11 in the composition is equal to 1 x 1 〇 2 to 1 x 1 〇 ii cfu / g of the dry composition. This includes the case where the bacterium is viable, inactive or dead or even in fragments such as DNA or cell wall material. The possibility of existence. In other words, the amount of bacteria contained in the formula is expressed as the colony forming ability of bacteria in which all bacteria are living bacteria, regardless of whether the bacteria are actually alive, inactive or Dead, fragmented, or a mixture of any or all of these states 163796.doc 201247111 Status. Preferably, the amount of probiotics is equal to 1×10 to 1×10 〇9 cfu/g of dry composition for administration of the desired or sprayed milk precursor, and even more preferably equal to 1>< 106 to ^108 (^/8 dry composition) The amount of probiotics in the dry composition of the progeny administered per gram can be reduced and the daily dosage as described above should be emphasized. Administration method: (1) administration of the parent to be produced: the composition can be administered to the parent to be produced by various methods, as long as The composition may be in contact with the gastrointestinal tract of the female. The composition is preferably administered orally as part of a food, beverage or dietary supplement of the parent to be produced. The composition may also be administered as a pharmaceutical composition. Oral administration is preferred. However, in the case of pathological conditions or when additional enteral meals are used, the administered composition can be added to the enteral feeding. (ii) Investing in newborn progeny: ST11 can also be alone ( In pure form or diluted with water or mother milk, for example, as a food supplement or as an ingredient in infant formula, it can be directly administered to the offspring. The formula can be a baby "premature formula" (if the offspring are born before the full term) Or out "lower"), "starter formula" or "follow-on formula". Formulated milk may also be hypoallergenic (HA) formula, in which cow's milk protein is hydrolyzed protein. An example of the nascent infant formula is provided in Example 2. In one embodiment of the invention, ST11 or a composition comprising ST11 or a composition comprising ST11 is administered to the infant via a lactating mother. The lactating mother is as described above. ST11 or a composition containing ST11. Xianxin is in a certain 163796.doc • 15- 201247111 In some cases, ST11 can pass the benefits to the baby via human breast milk. The bond is not accepted, and the benefit is directly passed to ST1. Milk is delivered to the infant either indirectly by transferring ST11-induced compounds or metabolites to human breast milk or by modulating the amount of breast milk from immunomodulatory compounds such as immunoglobulins, soluble CD 14, TGF-β or cytokines. In one embodiment of the invention, ST11 is administered to the infant via human breast milk administered to the lactating mother of ST 11. In one embodiment, ST11 is administered to the lactating mother and S The beneficial effects of T11 are transmitted to the infant by human breast milk (for example, by the ST11-inducing compound in the mother). Administration with other compounds: ST11 can be administered alone (in pure form or diluted with water or milk (including, for example, breast milk) or Administration of a mixture of other compounds (such as hunger supplements, nutritional supplements, pharmaceuticals, carriers, fragrances, digestible or non-digestible ingredients). Vitamins and minerals are examples of typical dietary supplements. In the embodiments, the composition is administered together with other compounds that enhance the effect of immunization of the progeny. The synergistic compounds may be useful for facilitating the delivery of ST11 to the gut of the parent to be produced or may otherwise enhance the composition for the sub A carrier or matrix that acts on behalf of the immune system. Such compounds may be other active compounds that synergistically or separately affect the immune response of the infant and/or enhance the action of the probiotic. An example of such synergistic compounds is maltodextrin. One of the functions of maltodextrin is to provide a carrier for probiotics, enhance their action, and prevent aggregation. Other examples include known probiotic germinating compounds, such as carbohydrates selected from the group consisting of 163796.doc -16 · 201247111; inulin, fructooligosaccharides (FOS), short chain fructooligosaccharides (short chain FS), Galactose oligosaccharide (G0S), xylooligosaccharide (x〇s), neuroglycoside 曰# knife hydrolyzed guar gum (PHGG) acacia gum (acacia gUm), soy gum, apple extract, lactose (lact〇) W〇lfberry), 枸杞 extract or a mixture thereof. Other carbohydrates may be present, such as a second carbohydrate that acts synergistically with the first carbohydrate, and are selected from the group consisting of xylooligosaccharides (X0S), gums, gum arabic, starch, partially hydrolyzed guar gum. Or a mixture thereof. The amount of the plurality of carbohydrates may be from about 1 g to 20 g, or from 1% to 8% by weight of the daily dose of the composition, or. to. Alternatively, the carbohydrate content is from 1% to 8% by weight of the dry composition. The daily dose of carbohydrates and all other compounds with ST11 should always comply with published safety guidelines and regulatory requirements. This is especially important for the birth of newborn babies. In one embodiment, the nutritional composition preferably comprises a source of protein. Dietary proteins are preferred as a source of protein. The gestation protein may be any suitable dietary protein, such as an animal protein (such as a milk protein or a meat protein plant protein (such as soy protein, wheat protein, rice protein or legume protein), a mixture of free amino acids, or a combination thereof. Milk protein of protein and milk protein is especially preferred. / In the study, it is recommended that the baby will be sensitized during the weaning period (ie 3 to 7 months after birth), and the baby will still accept at least Partial breastfeeding. We firmly believe that Chuan (10) and infants (via breastfeeding or by direct administration) help to introduce sensitizing foods (such as milk proteins) into children's foods. 163796.doc 201247111 The composition may also comprise a source of carbohydrates and/or a source of fat. If the composition of the invention is a nutritional composition and includes a source of fat, the source of fat preferably provides from about 5% to about 55% of the energy of the nutritional composition; for example, The energy of θ 200 / ◦ to about 50 ° /. The lipid constituting the fat source can be any suitable fat or fat mixture. Vegetable fat is especially suitable, such as soybean oil, palm Oil, coconut oil, safflower oil, sunflower oil, corn oil, rapeseed oil, lecithin and the like. Animal fat such as milk fat may be added if necessary. Other carbohydrate sources may be added to the nutritional composition. Preferably, from about 40% to about 80% of the nutritional composition energy is provided. Any suitable carbohydrate may be used, such as sucrose, lactose, glucose, fructose, corn syrup solids, maltodextrin or mixtures thereof. Dietary fiber "if added, preferably comprises up to about 5% of the energy of the nutritional composition. The dietary fiber may be from any suitable source including, for example, soy, pea, oat, pectin, guar gum, gum arabic, fructooligosaccharide Or a mixture thereof. Suitable vitamins and minerals may be included in the nutritional composition in an amount that meets appropriate guidelines. One or more essential long chain fatty acids (LCpUFA) may be included in the composition. An example of an LC-PUFA that may be added is twenty-two. Carbahexaenoic acid (DHA) and arachidonic acid (AA) may be added to a concentration of LC_puFA so that it constitutes more than 0.01% of the fatty acid present in the composition One or more food grade emulsifiers may be included in the nutritional composition if desired; for example, monoglycerides and diglycerides of diterpene tartrate, lecithin and mono or diglycerides or mixtures thereof, similarly, may include suitable salts And/or stabilize 163796.doc -18- 201247111. The fragrance can be added to the composition. During the administration period: Once the mother is aware of the pregnancy, it can start to obtain the gluten. Before the start, for example, if the female tries to silk, the drug can start at any time after the start of the surname. It can start at the relatively late time in (4), in the case of human (4), preferably in the case of surname 3, 4, 5, 6, 7 or 8 months, or for other mammals in the corresponding period, or up to two weeks before the expected date of delivery. The administration period can be continuous (for example, until weaning and includes breast-feeding to weaning) or discontinuous. Preferably, the continuous administration of the drug is (4) a more permanent effect 1 and it is speculated that the discontinuous mode (e.g., administered daily every week or every other week) induces a positive effect on the offspring. The duration of the drug can vary. Although a positive effect is expected under a relatively short duration of administration (eg, a newborn is administered daily for a week and adults are administered daily for one or two months), a longer duration provides a potentiating effect (eg, in humans) Duration of 3, 5 or 8 months and corresponding period in other mammals). Administration should cover at least a portion of the gestation period and at least a portion of the lactation period, or an equal period of time when the newborn is not breastfed. Preferably, the period of administration of the parent to be born covers a substantially full length of gestation, but this period may be shorter. Similarly, the period of administration of the mouth-nosed mother body preferably covers substantially full-length lactation, but this period may also be shorter. Preferably, the parent is administered by daily ingestion (one or two times per day) or weekly (one or two times per week). 163796.doc 201247111 ST11 can be directly administered to infants. This is especially true if the mother has not been breastfed or the mother has stopped breastfeeding. However, infants who are breastfed can also receive ST11 by direct administration. Infants can be administered through breastfeeding or by direct dosing or both, to 6 months of age or even 1 year of age. Therefore, if breastfeeding, ST11 can be administered during breastfeeding or after partial or complete weaning. Preferably, the infant is administered by daily ingestion (one or two times per day) or weekly (one or two times per week). Effect of administration of probiotics: It has been surprisingly found that ST11 is administered to the progeny of the mother to protect against progeny. In at least another study, it has been found that ST11 does not exhibit effects or exhibits very low effects in the prevention of allergies: for example, in Vaccine 29 (2011) 1981-1990 (available online 7/1/2011), I. Schabussova Etc. In a mouse model of grass and birch pollen allergen multi-sensitization, intranasal administration of ST11 did not protect mice in a prophylactic mode (before sensitization), while NCC3011 (B. iowgww) ) can protect. In the same paper, mice were provided with ST11 and NCC3001 to manage symptoms (when sensitizing and attacking). The conclusion of this paper is that the selection and timing of probiotic strains is critical for immune tolerance induction. It is now well established and recognized that not all probiotic species or strains have similar effects and characteristics regarding immune regulation or allergy. See, for example: -Van Hemert S, Meijerink M, Molenaar D, Bron PA, de Vos P, Kleerebezem M, Wells JM, Marco ML. Identification 163796.doc -20- 201247111 of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood Mononuclear cells. BMC Microbiol· November 16, 2010; 10:293. -Meijerink M, van Hemert S, Taverne N, Weis M, de Vos P, Bron PA, Savelkoul HF, van Bilsen J, Kleerebezem M, Wells JM. Identification of genetic loci in Lactobacillus plantarum that modulate the immune response of dendritic cells using Comparative literature hybridization. PLoS One. May 13, 2010; 5(5): el0632. Therefore, in general, it can be said that probiotics have no or only predictable effects on the allergic effect, and only the target experiment can prove these effects. Without being bound by theory, the effect of administering ST11 to a pregnant mother and its progeny can be illustrated by the delivery of compounds and/or metabolites induced by ST11 and/or ST11 to the infant. This delivery can occur in the uterus and can be further synergistic (e.g., intensive) with ST11 after birth. However, the exact mechanism of this transmission remains the goal of ongoing scientific research. Thus, according to the present invention, the positive effects of ST11 can be initiated in the very early stages of life (in the uterus) of the infant during critical immune or intestinal development, and extended to the maturity stage after birth. β is administered to the maternal progeny of the mother. In order to avoid allergies. Thus, the allergic reaction (in this case the allergen-specific recall response) of the progeny of the parent sensitized with a particular allergen and then treated with ST11 challenged with the same allergen is reduced compared to the progeny of the untreated parent. . Similarly, when stimulated with mitogens, a reduced degree of immune response (i.e., non-specific reaction) is observed in the progeny of the treated parent. 163796.doc -21· 201247111 In one embodiment of the invention, the parent ST11 is administered to reduce air sensitization (eg, birch pollen) sensitization (for an overview of the study, see Example 1, Circle) and then by the same allergen attack Inflammation of the trachea in the progeny of venom. This condition can be manifested as a lower infiltration of eosinophils into the trachea than sensitized and untreated progeny from the parent treated with ST11 (see Figure 3A). The inventors also showed that maternal ST11 supplementation did not have an adverse effect on the ability of offspring to fight infection. Although the number of eosinophils (such eosinophils are directly involved in the initiation of allergic reactions), the bronchoalveolar progeny of Example 1 The number of macrophages and lymphocytes in the lavage (BAL) solution was not affected compared to the progeny of the parent without ST11 treatment (see Figure 3A). Histological analysis of the lung sections revealed that contrary to the progeny of the control parent, ST1 The progeny of the mother of the sputum treatment reduced tracheal inflammation, goblet cell metaplasia, and mucus production (see Figure 2). The progeny of control mice exhibited bronchial and perivascular gauges. Cell infiltration (Fig. 2B, Fig. 2E). Significant reduction in inflammation around the bronchi with rare mononuclear cell infiltration was detected in progeny derived from ST 11 exposed mothers (Fig. 2C, Fig. 2F). There was no impregnation in the lungs of the animals (Fig. 2A, Fig. 2D). Consistently, periodic acid-Schiff (pAS) staining of the lung sections revealed a comparison with the parental control group receiving water instead of ST11 (Fig. 2E). The occurrence of goblet cell hyperplasia and mucus hypersecretion in the progeny of the ST11-treated mother was strongly reduced (Fig. 2F). The lung sections from untreated mice showed no secretion of mucus (Fig. 2A, Fig. 2D). The data indicates that maternal exposure to ST11 causes mucosal immune response changes in the progeny, such that subsequent stimulation with the allergen causes distal tracheal inflammation. In another embodiment of the invention, the parent is administered ST1丨 to reduce airborne 163796.doc • 22· 201247111 Allergens (eg Bet v 1) sensitized (Example 1) and then BAL fluid (Fig. 3B), lung (circle 3C) and lung-associated lymph nodes in mice challenged with birch pollen aerosol (Fig. 3D) The content of the interleukin 5 (lL-5). The content of IL-5 in the progeny of the STU-treated parent was significantly higher. Therefore, maternal administration of sT11 reduced the allergen-specific recall response in the progeny. In order to supplement the parental ST11 in the progeny by changing the cell Th1/Th2 balance test Whether a permanent immunoblot can be obtained, the spleen cells of the sensitized and challenged progeny are stimulated with Bet v 1. Observed in spleen cells from progeny of the parent supplementing st 11 compared to progeny derived from the control parent The secretion of Th2 cytokines (IL_4 and IL-5) was significantly lower (Fig. 4A, Fig. 4B). In addition, spleen cells from progeny of the near-term sham-treated (control group) were stimulated in vitro with Bet v 1 in the presence of ST11. Bet v 1 induced IL-4 and IL-5 were significantly reduced (Fig. 4C, Fig. 4D). The inhibitory effect of Sti 1 on il_5, which is critical for the recruitment and survival of eosinophils, provides a mechanistic explanation for the reduction in tracheal eosinophilia in the progeny of the ST11-treated mother. Therefore, maternal administration of ST11 reduces allergen-specific recall responses. In another embodiment of the present invention, the maternal administration of ST1丨 reduces birch pollen sensitization and is stimulated by mitotic protoxin A (c〇n A) progeny splenocytes to interleukin 5 (IL-5) Secretion amount (Example υ. c〇na is a lectin known to stimulate a subset of tau cells to produce functionally different tau cell populations (Dwyer et al., (1981), C7z'n 46(2): 237-249). The IL-4 content remained unchanged (see Figure 5A, Figure 5B). Thus, maternal supplementation with ST11 reduced mitogen-induced winter immune responses to 163796.doc •23·201247111 and allergen-specific cellular immune responses. The inventors have found Supplementation of s τ 11 during the delivery period reduced allogeneic induction and mitogen-induced spleen and mesenteric lymph node (MLN) cells in vitro (as shown in Figure 5C and circle 5D). Therefore, this indicates that the mother can use sti 1 Producing a complete blot of the immune system of newborn mice, modulating the cellular response following antigen-specific and non-specific stimulation. According to the present invention, reducing or preventing the occurrence of allergic immune responses in the progeny of the ST11-treated mother can reduce or prevent Airborne Allergens, food allergens or allergic immune reactions in contact with allergens (such as nickel). Airborne allergens can be indoor dust mites, animal dander and tree and grass pollen, especially birch pollen. Bet v 1, Bet v 2 profUins and cross-reactive carbohydrate determinants (CDD) are known birch pollen allergens. According to the invention, the reduction or prevention of allergic immune reactions occurs in the progeny of the ST11-treated parent. It can reduce or prevent allergic immune reactions to allergens that are cross-reactive with birch pollen. These allergens may be food allergens such as apples and stone fruits that may contain allergens that are cross-reactive with Bet V 1 . , celery, carrots, nuts, and soybeans. These allergens may also be peaches, lamps, articles, 'strawberries, persimmons, winter squashes, and carrots that are known to be reactive with Bet v 2 allergens. According to the present invention, The reduction or prevention of allergic immune reactions in the progeny of the processed mother can be reduced by at least 5%, more preferably 10%, and even more preferably at least 30% compared to the progeny of the untreated parent. And the best is at least 5%. ST11 is a probiotic 163796.doc -24- 201247111 isolated from the fecal microbes of breast-fed children. Therefore, the attempt to simulate the health promotion of breast-feeding children/biological organisms as close as possible Strategy, especially for non-breastfeeding|Children's administration ^ can provide superiority to the mother (four) h children's towel unscented other _ strain advantage \ Example 1: The mouse model using birch pollen allergy indicates that the maternal supplement ^ STu will protect the offspring To avoid an allergic phenotype. BALB/c mice receive ST11-containing drinking water daily during the last week of pregnancy and during lactation. Pregnant and lactating female mice are fed daily with drinking water containing live probiotic strain ST11. The progeny of the ST11-treated parent or pseudo-treated parent was sensitized with the recombinant primary birch pollen allergen Bet v丨 and challenged with birch pollen extract (Fig. 1 experimental design). Animals: Column BALB/c mice (day 14 of pregnancy) were purchased from Charles River (Sulzfeld, Germany) and maintained under conventional captive conditions. Female TLR2 and TLR4 deficient mice with a C57BL/6 genetic background and wild type mouse lines were obtained from the University of Veterinary Medicine of Vienna (Austria). All experiments were approved by the Animal Experimentation Committee of the University of Vienna and the Federal ministry of Science and Research. 0 Probiotics: Probiotic ST11 is Lactobacillus paracasei NCC 2461 CNCM 1-2116 (Lactobacillus paracasei) and belongs to the Nestlé Research Culture Collection (Nestl0)

Research Center bacterial collection) (Lausanne, Switzerland). 163796.doc -25· 201247111 For oral administration during the perinatal period, spray-dried bacterial preparation diluted with drinking water. For in vitro experiments, the Lactobacillus paracasei formulation was not activated for 3 hours at room temperature with 1% furfural-PBS, washed twice with sterile PBS, and stored at -20 eC. Near-term ST11 exposure: starting from the third trimester (day -7) and continuing throughout the lactation until the day of weaning (day 21), pregnant BALB/c mice receive 5xl08 cfu/ml ST11 per day The drinking water (average sputum dose was 2 XIO9 cfu per mouse) for a total of 4 weeks (experimental design; Figure 1). Age-matched control animals received only water. The presence of ST11 in the feces was tested by PCR analysis. DNA was prepared from stool samples and amplified using ST11-specific PCR primers. As expected, ST 11 specific PCR products were only detected in maternal mice from ST11 treatment, but not from control maternal mice (data not shown). The stool samples of the progeny were collected at the 21st day (weaning). PCR analysis revealed the absence of ST11 in the progeny of the parent or control parent treated with ST11 (data not shown). Sensitization and challenge of the offspring: On the 21st, 35th and 49th days, the total volume of 150 μΐ was emulsified in Hydroxide (like, Serva, Heidelberg, Germany). 1 Recombinant main birch pollen allergen Bet v 1 (rBet v 1 ; Biomay, Vienna, Austria), subcutaneous (sc) sensitization of the progeny of maternal mice from near-term ST 11 exposure or control treatment (experimental design; Figure 1). To induce tracheal inflammation, one week after the last sensitization, exposure to aerosolized 丨% birch pollen extract (BP; Allergon, valinge, Sweden) for two consecutive days (56th to 163796.doc • 26·201247111 57 days) Attacking mice. Mice were anesthetized with Sevofluran (Abbott, Vienna, Austria) 72 hours after the final tracheal challenge (Day 60). BAL and cell sorting counts: Progeny from maternal mice treated with ST11 or control were finally anesthetized, and BAL was collected twice using 2 ml of PBS containing a protease inhibitor cocktail (Roche, Mannheim, Germany). Total white blood cells were counted and cytospin (Shadon Cytospin®, Shadon Southern Instruments, USA) was stained with hematoxylin and eosin (H&E; Hemacolor®, Merck, Darmstadt, Germany). Cell types were identified using standard morphological criteria and 200 cells were counted per centrifugation smear via light microscopy. Cell-free supernatants were stored at -20 °C for further analysis. Lung histology: Whole lungs were removed from the mice and fixed with 10% brewing-PBS for histological analysis. Tissue sections embedded in Dendrobium were stained with H&E. Tracheal mucus obstruction was analyzed for the mothoic acid-Schiff stain (PAS, Sigma-Aldrich) section. Ex vivo stimulation of cell cultures: Spleen, lung, lung mediastinal draining lymph nodes (lung LN) and mesenteric lymph nodes (MLN) were collected after sacrifice and single cell suspensions were prepared from all organs. Which indicates 'in a 96-well plate at 37 ° C in medium ( supplemented with 1% heat-inactivated FCS, 2 mM L-glutamine, 100 U/ml penicillin, 1 〇〇pg/mi streptomycin) In RPMI 1640), cells (2.5 x 1 〇 7/ml) were stimulated with rBet v 1 (10 gg/mi) or concanavalin a (ConA) (1 pg/m Sigma-Aldrich) for 72 hours. As a control, cells were cultured alone. Spleen 163796.doc -27· 201247111 and MLN cells were determined by scintillation counting after adding 3[H]-thymidine for the last 18 hours (per 5.5 μ (:ί, Amersham, Buchter, Braunschweig, Germany) The proliferative response of the culture. In addition, to study the immunomodulatory potential of ST11 in vitro, the progeny splenocytes of the pseudo-treated parent were incubated with a mixture of ST11 (107 cfu/ml) and rBet v 1 (10 pg/ml) for 48 hours. Hormone measurement: The levels of IL-4 and IL-5 were measured using an ELISA kit (Endogen, Cambridge, ΜΑ) according to the manufacturer's instructions. Statistical analysis. All data are shown as mean SEM. Using Graph Prism The software (Graph Pad Softwar, Inc, San Diego, CA) and the non-parametric Mann-Whitney U-test analyzed the significance. It is considered that there is a significant difference when ρ < 0·05. Example 2: The following provides An example of the composition of an infant formula used in the present invention. This composition is given for illustration only. The protein source is a conventional mixture of whey protein and cool protein. Nutrient per 100 kcal per liter of energy (kcal) 100 670 protein (g) 1 .83 12.3 Fat (8) 5.3 35.7 Linoleic acid (g) 0.79 5.3 Alpha-linolenic acid (mg) 101 675 Lactose (g) 11.2 74.7 Probiotics (100% GOS) (g) 0.64 4.3 Minerals (g 0.37 2.5 Na (mg) 23 150 163796.doc -28 - 201247111 K(mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P(mg) 31 210 Mg (mg) 7 50 Mn(Kg) 8 50 Se(4) 2 13 Vitamin A (gg RE) 105 700 Vitamin D (pg) 1.5 10 Vitamin E (mgTE) 0.8 5.4 Vitamin ΚΙ (pg) 8 54 Vitamin C (mg) 10 67 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1.0 Terminal acid (mg) 1 6.7 Vitamin B6 (mg) 0.075 0.50 Folic acid (Kg) 9 60 Pantothenic acid (mg) 0.45 3 Vitamin B12 (pg) 0.3 2 Biotin (pg) 2.2 15 Biliary test (mg) 10 67 Fe (mg) 1.2 8 i(pg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 Lactobacillus paracasei NCC 2461 (ST11; see experimental section) per gram of powder 2xl07cfii 163796.doc -29- 201247111 [Simple description of the diagram] Figure 1: Experimental design to demonstrate maternal complementation of Lactobacillus paracasei ST11 to protect progeny from an allergic phenotype of birch pollen allergic experimental mouse model (female BALB) /c mouse; n = 8). Figure 2: Hematoxylin and eosin (H&E) stains (Figure 2A, Figure 2B and Figure 2C) and used acid-Schiff-stained (PAS) Figure 2D, Figure 2E, and Figure 2F) stained fixed whole lung paraffin embedded sections. Figure Α and Figure D correspond to non-sensitized/non-infected and non-probiotic-treated mice; Figure B and Figure E correspond to mice sensitized with Bet v 1 and challenged with birch pollen; Panel E corresponds to mice sensitized with Bet v 1 and challenged with birch pollen and treated with Lactobacillus paracasei ST11 in the near-term. Figure 3: Pneumonia in progeny mice The effect of ST11 near-term treatment on pneumonia. Figure a shows cell infiltration (macrophage, lymphocytes, neutrophils, and eosinophil counts) in the bronchoalveolar lavage (BAL) fluid of the offspring. Figures B, c and D show the content of interleukin 5 (il-5) in BAL fluid, lung and lung mediastinal drainage lymph nodes, respectively. The white band corresponds to the progeny of the parent (Birch pollen sensitized and challenged) which was not treated with Lactobacillus paracasei ST11. The black band corresponds to the progeny of the mother treated with ST11 (birch pollen sensitization and challenge). Figure 4: Cytokine production after spleen cell stimulation in vitro sensitization of the sensitized and attacked progeny (black band) from the parent of Lactobacillus sp. ST11 supplementation compared to the sensitized and attacked from the control parent Ex vivo allergens of the toxic progeny (white 163796.doc -30- 201247111 color band) re-stimulate the content of Th2 cytokines IL-4 (A) and IL_5 (B) secreted by spleen cell culture. Re-stimulation of Th2 cytokines il_4 (c) and IL-5 (D) secreted by splenocyte cultures by rBet vi (i〇^/mi) "Using false (control) treatment of spleen of maternal offspring Cell evaluation of the immunomodulatory potential of Lactobacillus paracasei ST11: Splenocytes were incubated with Lactobacillus paracasei ST11 (108 cfu/ml) mixed with -rBet v 1 (10 Kg/ml) for 48 hours. Figure 5: Spleen cell departure The cytokine production after body stimulation is derived from the mother of ST11 (black band) or from control mice (white band) by sensitization with birch pollen and with mitotic procyanidin A (concanavalin A, Con A) The content of il-4 (A) and IL-5 (B) secreted by splenocytes of the progeny of the progeny. Allergen-induced (Bet v 1) or ConA-induced (ConA) spleen cells isolated from the progeny of Lactobacillus paracasei ST11 treated (black strips) or mothers not treated with Lactobacillus paracasei ST11 (white strips) Ex vivo proliferation of C) and MLN (D). 163796.doc •31·

Claims (1)

201247111 VII. Patent application scope: 1. A sub-dry laccase ([α£τίο6αοζ_//Μ5 piiracfliei) NCC 2461 (ST11), which is used to give birth to the parent and to the parent. The offspring are used to reduce or prevent offspring from developing an allergic immune response. * 2. The Lactobacillus paracasei NCC 2461 (ST11) of claim 1, wherein the parent is extended to the lactation period of the progeny or/and the progeny is administered via the breast milk of the mammal. . 3. The Lactobacillus paracasei NCC 2461 (ST11) of claim 1 or 2, wherein the progeny are at risk of an atopic disease. 4. The Lactobacillus paracasei NCC 2461 (ST11) of claim 1 or 2 or 3, wherein the allergic immune response is directed to food and/or airborne allergens. 5. The Lactobacillus paracasei NCC 2461 (ST11) of claim 4, wherein the allergic immune response is directed to airborne allergens, particularly birch pollen allergens Bet v 1 and Bet v 2 . 6. The Lactobacillus paracasei NCC 2461 (ST11) of claim 4, wherein the allergic immune response is cross-reactive with a tree allergen (preferably birch pollen allergens Bet v 1 and Bet v 2) Sexual food allergens. 7. The Lactobacillus paracasei NCC 2461 (ST11) of claim 6, wherein the food allergen is apple, pear, stone fruit, celery, carrot, nut and/or soybean. 8. A Lactobacillus paracasei Nc (: 2461 (ST11), wherein the allergic immune response may be an allergen-specific recall response or a non-allergen-specific immune response. 163796.doc 201247111 9. Lactobacillus paracasei NCC 2461 (ST11), wherein the reduction in these allergic immune responses in the #progeny is (0 in the case of an allergen-specific recall reaction, reducing the production of IL 4 and IL-5, and/or (u) In the case of a non-allergen-specific immune response, a decrease in IL-5 is produced, which is a response to the progeny of the parent not treated with ST11. 10. As in items i to 9 Any of the Lactobacillus paracasei NCC 2461 (ST11) 'where the ST11 is administered to the mother to be produced for at least two weeks prior to delivery, and the progeny are administered directly or via the mother's milk for at least 2 months after splitting. Jia Changda 6 months after delivery. 11 A solution of Lactobacillus paracasei NCC 2461 (ST11), wherein the ST11 is preferably administered orally to the waiting or lactating parent in the form of a food 'beverage, dietary supplement or pharmaceutical composition. Claim No. 5, Lactobacillus paracasei NCC 246 (ST"), wherein the ST11 is administered by the mother's milk via the progeny or as a supplement in its pure form or diluted with water, breast milk or infant formula. 13. The Lactobacillus paracasei nCc 2461 (ST11) according to any one of the preceding claims, wherein the ST11 is ix1〇6 to 1χ1〇ιι cfu, preferably 1χ1〇8 to 1X10 Cfu (cfu is formed by the community) The dose of the unit is administered to the expectant or lactating mother. 14. The Lactobacillus paracasei NCc 2461 (stii) according to any one of claims 1 to 12, wherein the stii is ixl02 to 1χ1〇ι〇, preferably 1χ1〇2 to 163796.doc •2· 201247111 1x10 cfu (Cfu is a community forming unit) daily dose is administered to such progeny. 15. Lactobacillus paracasei nCC 2461 (stii) according to any of the preceding claims 'Where the ST11 is packaged per gram of dry composition A composition of from 1 to 2 to 8 cfu is administered to the parent or infant. 16. A Lactobacillus paracasei ncc 2461 (ST11) according to seq. 15, wherein the composition comprises other components preferably selected from the group consisting of Or probiotics: inulin, fructose (FOS), short-chain fructooligosaccharides (short-chain I〇s), galactooligosaccharides (GOS), xylooligosaccharides (x〇s), neuroglycosides , partially hydrolyzed guar gum, gum arabic, soy gum, milk (Lact〇w〇lfberry), alfalfa, apple extract or a mixture thereof. 17. Lactobacillus paracasei ncc (ST11) according to any of the preceding claims, wherein the ST11 has not been activated so that it is not replicable. 18. A composition comprising Lactobacillus paracasei ncc 2461 (ST11) for use in a primary prevention or reduction of an allergic immune response in an infant, the method comprising: administering to a surrogate female prior to delivery A daily dose of Lactobacillus paracasei NCC 2461 (ST11) for at least two weeks, and after delivery, a daily dose of live probiotics to a lactating woman or newborn infant for at least 2 months, preferably up to 6 months after delivery Or leap years. 19. The method of claim 18, wherein after the delivery, Lactobacillus paracasei NCC 2461 (STU) is administered to the newborn infant via the lactating mother. 20. The method of claim 18 or 19, wherein the daily dose administered to the expectant or lactating mother is from about 1 x 10 6 to 1 x l 〇 n cfu, preferably 1 < 1 〇 8 to 1 < 1 〇丨. He (cfu is a colony forming unit) of sti 1. The method of claim 18 or 19, wherein the dose of the progeny administered to the progeny is about 至2 to lxl01G, preferably lxlO2 to lxlO4 cfu (cfu is a colony forming unit) of Lactobacillus paracasei NCC 2461 (ST11). 163796.doc -4-