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WO1994026114A1 - Procede de stimulation et de modulation du systeme immunitaire d'animaux a l'aide de compositions microbiennes - Google Patents

Procede de stimulation et de modulation du systeme immunitaire d'animaux a l'aide de compositions microbiennes Download PDF

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Publication number
WO1994026114A1
WO1994026114A1 PCT/US1994/005414 US9405414W WO9426114A1 WO 1994026114 A1 WO1994026114 A1 WO 1994026114A1 US 9405414 W US9405414 W US 9405414W WO 9426114 A1 WO9426114 A1 WO 9426114A1
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bacteria
macrophage
oropharyngeal
apathogenic
animal
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William E. Marshall
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Immunom Technologies Inc
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Immunom Technologies Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/05—Immunological preparations stimulating the reticulo-endothelial system, e.g. against cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • this invention relates to a method of stimulating oropharyngeal-alveolar macrophages in animals or humans by administering effective amounts of
  • apathogenic bacteria selected from the family of Lactobacillaceae to prevent or reduce infections.
  • Macrophages sometimes called "sentry cells,” are large phagocytic cells of. t ⁇ e reticuloendothelial system which engulf and digest or phagocytize, cells, microorganisms or other foreign materials in the bloodstream and tissues of humans and animals.
  • animal refers to humans and animals, and includes mammals, birds and fish.
  • Macrophages reside in tissues where infections can originate such as in the oral, pharyngeal and alveolar cavities, the gastrointestinal tract, urethra, vagina, etc. It is believed that during their evolution and exposure to natural immunogens, macrophages begin producing cytokine-based signals that report the nature of the immunogen to the associated immune system, as well as certain organ tissue cells. sampling by macrophages of microbes, pathogens and other foreign materials includes
  • MHC major histocompatibility complex
  • macrophages survey the host's internal and external environments, and through the release of approximately 75 different molecules, are capable of both
  • T-cells thymocytes
  • T-cells in turn, signal their response as an alert to additional cells of the immune system.
  • Circulating monocytes are found within the peripheral blood and lymph. These cells phagocytize aberrant molecules
  • tissue synthesized by the host or tissue fragments resulting from wounds or tissue breakdown. Certain tissues also have associated mature macrophages exercising the same roles.
  • Interleukin-1 is a hormonal peptide released by animal macrophages as an alert signal to T-cells and other immunocytes as well as tissues of the host. The synthesis of IL-1 is induced when foreign materials are phagocytized by a
  • IL-1 and other cytokines released by the macrophage are thought to present a profile regarding the nature of the invader which has been impressed over time into the memories of the immunocytes receiving the signals.
  • IL-6 tumor necrosis factor
  • TNF tumor necrosis factor
  • LPS lipopolysaccharide
  • lipid A consisting of three covalently linked parts: lipid A,
  • polysaccharide core and O-antigens The structures of lipid A and the polysaccharide core are well-conserved between and among Gram-negative bacterial genera and species.
  • the O-antigen region differs markedly between species and can be changed by mutation at a high frequency within the same species, a condition called "phase variation".
  • the macrophage is capable of sending an "acute phase" signal after detecting life-threatening levels of pathogens, LPS and other microbial components.
  • This acute phase signal is believed to activate thymocytes and other cells through the multiplicity of interleukins which it can release, e.g. IL-1, IL-6, TNF, etc.
  • U.S. Patent No. 4,975,467 teaches methods by which synthetic compounds can be used to inhibit the release of IL-1 and thereby alleviate its mediated pathophysiological conditions.
  • U.S. Patent No. 4,975,467 teaches methods by which synthetic compounds can be used to inhibit the release of IL-1 and thereby alleviate its mediated pathophysiological conditions.
  • Patents Nos. 4,849,506 and 5,082,657 illustrate the importance of cytokines in communicating between cells as shown by the use of leukoregulin to regulate tumor growth.
  • U.S. Patent No. 5,055,447 provides methods and compositions for the treatment or
  • That patent illustrates the complexity of the cytokine signals for thymocyte mitogenesis and teaches the use of a complex mixture of cytokines and other pharmacologically active compounds for control of shock.
  • U.S. Patents Nos. 5,041,427 and 5,158,939 teach the use of naturally occurring non-toxic LPS from R. spaeroides , ATCC 17023, to protect animals from toxic LPS.
  • U.S. Patent No. 5,157,039 supports the clinical need for controlling IL-1 release by macrophages by teaching the use of 2-quinolinyl methoxy compounds to inhibit a family of
  • U.S. Patent No. 5,082,838 teaches the use of sulfur-containing fused pyrimidine derivatives to inhibit IL-1 release to aid in the prevention of inflammation resulting from bactremic infections.
  • the acute-phase response of a macrophage to LPS or its constituent, lipid A is believed to represent a response to an unbalanced stimulus rather than to an entire microbe.
  • This unbalanced stimulus is thought to result in an unbalanced cytokine signal which ultimately results in a pathophysiological state: septic shock marked by fever, inflammation and typically death of the host.
  • the macrophage itself can be rendered unbalanced giving enhanced toxicity to Gram-negative pathogens, such as E. coli and S. typhimurium. Therefore, it is important to maintain the condition of the macrophage and not subject it to components of microbes but rather to the entire organism.
  • TNF tumor necrosis factor
  • IL-6 tumor necrosis factor-6
  • Cytokine production has been induced by exposing macrophages to cell components of a number of Gram-positive pathogens and non-pathogens as well, (Bhakdi, et al., Infec. & Immun. 59:
  • Cytokines are multifunctional with at least dual roles in infections. Certain levels are correlated with the fatal outcome of septicemia in humans, while others indicate their role as mediators of septic shock.. In addition the macrophage response can differ among a number of biochemical pathways, (Kantengwa, et al.. Infect. & Immun. 61: 1281-1287, 1993). Selective profiles of cytokine production has been shown in human urinary tracts infected with E. coli, (Agace, et al., Infect. & Immun. 61:
  • apathogenic microorganisms at optimum levels, administered orally for the purposes of encountering antigen-sampling macrophages in the oropharyngeal cavity. Such methods would optimally enable the macrophage to remain functional in its response to pathogens.
  • Methods therefore useful in the balanced activation of an impaired immune system and or in the modulation of the macrophage response to pathogens would be of utility, not only in the maintenance of human and animal health, but also in decreasing salmonellosis in commercial poultry production, reducing reliance on sub-therapeutic doses of antibiotics in animal feeds, and maintaining human and animal cell-line cultures, as well as other uses.
  • U.S. Pat. No. 4,347,240 teaches the use of selected strains of L. caseii , YIT 9018, for treating and/or preventing tumor growth.
  • the daily effective doses were ideally 1 to 2 g/kg for oral administration. This amounts to 1.5 ⁇ 10 CFUs per day for a 180 lb. person. Besides being uneconomical, this is not a physiological dose and is toxic to the oropharyngeal macrophages as well as to tumor cells.
  • U.S. Pat. No. 3,953,609 teaches the use of a strain of L. lactis , NRRL B-5628, to restrict the growth of undesirable bacteria in the mouth or crops of animals and fowl.
  • the amounts claimed are more than 1 ⁇ 10 10 CFUs per day per kg of body weight and for an extensive period of time. Again, these levels are unaffordable and, in addition, are believed to be dysfunctional to the host's macrophage population.
  • Lactobacilli The levels of recommended use were 20 g of dried
  • Lactobacillus as a drip twice daily for 21 consecutive days.
  • yogurt at a level of 4 ⁇ 10 11 twice daily per person.
  • NRRL-B-5628 at levels of 7.5 ⁇ 10 11 CFUs per day for up to 6
  • MALT mucosa-associated-lymphatic-tissue
  • bacterium (an apathogen) occupies an environmental niche at the expense of another (a pathogen), and further teaches the use of much higher levels of bacteria than the present invention.
  • the prior art does not address the use of special product formulations to deliver specific bacterial amounts directly to macrophage.
  • the prior art does not teach the use of these bacteria to activate and modulate the macrophages of the oropharyngeal cavity in a product form targeted to cells of that region.
  • L . bulgaricus and S . thermophilus at 2.4 ⁇ 10 11 CFUs were fed daily to mice for 29 days before challenge with S .
  • Peritoneal macrophages were shown to be activated by feeding 1 ⁇ 10 9 CFUs. of L. caseii and L. bulgaricus daily for 8 days to young mice as determined by increases in their enzymic activity and their ability to phagocytize colloidal carbon, (Perdigon, et al., Infect. & Immun. 53: 404-410, 1986). In these experiments, no attempt was made to target the macrophage population of the oropharyngeal cavity with lower levels of bacteria, based on ratios to macrophages, and in the absence of food.
  • the invention comprises methods and compositions for stimulating an animal immune system by administering an
  • apathogenic bacteria selected from the family Lactobacilliaceae in a ratio of between about 500:1 and 1:500 bacteria to
  • the macrophage being present in the oropharyngeal-alveolar cavity, in an acceptable carrier effective to deliver said bacteria to said oropharyngeal-alveolar cavity of the animal.
  • the ratio of apathogenic bacteria delivered to the macrophage in the oropharyngeal-alveolar cavity is between about 100:1 and about 1:100.
  • the ratio of bacteria to macrophage is between about 10:1 and about 1:10.
  • acceptable carrier it is meant that the vehicle which delivers the apathogenic bacteria to the oropharyngeal-alveolar cavity will do so in a form effective to enable a macrophage-bacteria interaction. Such interaction optimally induces a proper cytokine release.
  • Such acceptable carrier forms may comprise sprays, lozenges, gums, gels, and pastes.
  • the invention is especially useful for modulation of the macrophages response to activation by a pathogen and reduces the risk of septic shock in an animal upon exposure to a pathogen.
  • Macrophages from the lungs of mice (alveolar macrophages), from human peripheral blood (monocytes), and a cell line of human tumor origin (MonoMac 6), were used to study the interaction of apathogenic bacteria and macrophages.
  • these bacteria activate the quiescent macrophage as seen by microscopic observation (irregular shaping, clumping, granule formation), and the production of cytokines as measured by thymocyte mitogenesis.
  • the optimum ratios for activation lie between about 500 bacterial cells to 1 macrophage cell to 1 bacterial cell to 500 macrophage cells.
  • macrophage to E. coli or to LPS alone is marked by an enlargement of the macrophage typically referred to as an "angry" state.
  • the presence of apathogens modulates the macrophage response to typical clumping, but not an angry state of enlargement.
  • the method of the present invention comprises using certain apathogenic bacteria commensal to the host in proper levels to cause (1) . activation of the macrophages from a quiescent or impaired immune state and, (2) in the presence of these selected apathogens, modulation to normalcy the macrophage's response to a pathogen or components thereby ensuring that the macrophage ' s response will not lead to a pathological state of septic shock.
  • the macrophages can be of animal, fowl or fish origin.
  • the criteria for the selection of the modulating/activating bacteria are as follows: known apathogenicity, possessing a stable genome, and containing an A4alpha interpeptide bridge.
  • An A4alpha bridge describes the structure and linkage in the interpeptide bridge linking the two strands of peptidoglycan in the cell-wall or murein of Gram-positive bacteria.
  • the A4alpha consists of L-lysine covalently bonded to D-aspartic acid and in turn, covalently bound to L-alanine of the next peptidoglycan chain. L-lysine occurs in position 3 of the peptide stem descending from the muramyl residue and D-aspartic or
  • D-isoasparagine bridges it to L-alanine of the next peptide stem of the adjacent peptidoglycan polymer (Fig. 9 in Schleifer, et al., Bacter. Rev. 36: 407, 1972).
  • Fig. 9 in Schleifer, et al., Bacter. Rev. 36: 407, 1972 A review of the scientific literature (Bergey ' s Manual of Systematic Bacteriology. Williams & Wilkins, Baltimore, MD, 1986) indicates that these criteria are best met in the
  • Lactobacillaceae family of bacteria A number of these bacteria are indigenous to the oropharyngeal-alveolar cavity of animal and fowl, including humans and poultry. In addition, some have been used as ingredients in the preservation and product formulations of milk-based foods, and as such are considered
  • GRAS generally-regarded-as-safe
  • Lactobacillaceae family consists of 7 genera:
  • Lactobacillaceae Bifidobacterium indicum, coryne forme and eriksonii.
  • Lactobacillaceae Lactobacillus Thermobacterium acidophilus, bulgaricus, helveticus, jugurti, lactis, lactis, salivarius, delbruckii, leichmannii, and jensenii .
  • Lactobacillaceae Lactobacillus Streptobacterium caseii and sub-species, sake, coryneformis, curvatus, xylosus, and zeae .
  • Lactobacillaceae Lactobacillus Betabacterium fermentum.
  • Pediococcus cerevisiae, acidolactici, and pentosaceus .
  • the range of usefulness of these bacteria lies in their ratio to the macrophage. Very high doses are toxic, while very low doses do not provide for a modulated response or activation. Beneficial results are obtained within the ratio of bacteria to macrophage of about 500:1 to 1:500 and preferably 100:1 to 1:100. The optimum range is approximately from 50:1 to 1:50.
  • Ratios immediately outside of this range give uneven results. Delivering these ranges to receptive macrophages requires the formulation of products that can be held in the oropharyngeal-alveolar cavity rather than swallowed into the stomach and lower intestines. This necessitates the use of a medicament developed to insure that the active ingredients are held in the oropharyngeal cavity long enough to allow a
  • Such formulations can be sprays, lozenges, gums, gels, pastes, etc.
  • Such formulations can be sprays, lozenges, gums, gels, pastes, etc.
  • CFUs colony-forming-units
  • the bacteria can be administered as dead cells, the modulation is not as effective as when viable cells are used. If non-viable cells are employed, it is beneficial to maintain their surface antigens intact. This necessitates a "soft kill" of the bacteria by radiation, U.V. radiation techniques employing psoralens, mild heat, repeated freezing, etc. PREPARATION OF BACTERIA
  • Representative strains of the above-listed bacteria were obtained from national culture collections in lyophilized pure form and stored as directed on the labels.
  • E. coli strain 1090 hsdR was grown in trytone-soy-broth overnight and collected as described above.
  • Peripheral venous blood monocytes (mononuclear leukocytes) were separated from 40 cc of heparinized freshly-drawn blood by means of gradient-density centrifugation on Ficoll-Hypaque (Sigma Chemicals, St. Louis, MO). The buffy-coat was collected and washed once with fresh Ficoll-Hypaque and the cells counted in a hemocytometer and placed in an RPMI 1640 (GIBCO Labs., Grand Island, NY) buffer supplemented with 5% heat-inactivated (56°, 30 min.) fetal calf serum (Sigma Chemicals) and distributed in 0.5 ml aliquots in 24-well tissue culture plates. After a 3-hr.
  • the MonoMac6 macrophage cell line was maintained in RPMI buffer at 37°C in an atmosphere containing 5% CO 2 as described in Zeigler-Heitbrock, et al., Int. J. Cancer 41: 456-461, 1988, an equal quantity of fresh buffer was added every 48 hours. Cells were counted in a hemocytometer and distributed in 24-well tissue culture plates as described above.
  • Alveolar macrophages were collected by teasing murine lung tissue in RPMI buffer. Cells were counted in a hemocytometer and distributed in 24-well tissue culture plates as described above.
  • Selected macrophages were placed in a 24-well micropiate at a concentration of 1 ⁇ 10 5 cells per well. To these were added aliquots of the specific bacteria containing from 1 ⁇ 10 3 to 1 ⁇ 10 7 CFUs per well. This cellular mixture was incubated for 24 hours in the case of fresh peripheral blood monocytes or murine alveolar macrophages and for 48 hours in the case of the MonoMac6 cell line macrophages. This period of time permitted a generation of macrophage growth permitting the induction of synthesis of cytokines. After the doubling time, the
  • Cytokine release was quantitated in the frozen supernatants by the lymphocyte activating factor in the absence of exogenous stimulus. Each culture supernatant was tested at multiple dilutions in 24-well culture plates. The multiple dilutions were obtained by serial dilutions of one-third to a maximum of 12 dilutions or 1, 0.33, 0.11, 0.037, 0.0124, 1 ⁇ 10 -3 , 1.4 ⁇ 10 -3 , 4.5 ⁇ 10 -4 , 1.5 ⁇ 10 -4 , 5. ⁇ 10 -5 , 1.7 ⁇ 10 -5 , 5.5 ⁇ 10 -6 . The highest dilution in which radioactivity above the background was observed was considered the endpoint of stimulus.
  • Radioactive peaks reflecting thymocyte mitogenesis typically measured 3 to 25 fold higher than baseline controls.
  • the reciprocal dilutions were 1, 3, 9, 27, 81, 240, 730, 2190, 6560, 19680, 59050, 181820.
  • L. casei subspecies caseii ATCC 393, was grown overnight in 200 ml of MRS broth to a concentration of 1.0 ⁇ 10 9 CFU/ml, chilled rapidly, and centrifuged to a pellet. The pellet was washed three times with 200 ml of cold saline and finally suspended in 20 ml with a resultant concentration of 1.0 ⁇ 10 11 CFU/ml. Seven dilutions of the bacteria were made with cold saline and added to wells containing 8 ⁇ 10 5 of human peripheral blood monocytes at ratios of bacteria to monocytes ranging from 1250:1 to 1:800.
  • LPS lipopolysaccharide
  • the monocytes exposed to twelve bacteria and to one bacteria per monocyte cell were observed to phagocytize the bacteria and maintain their vigor during the exposure. Exposure of less than 1:1 ratios of bacteria to monocytes resulted in reduced mitogenesis of thymocytes. At a level of 1:8, only the first dilution demonstrated macrophage activation. The ratios of 1:80 and 1:800 yielded normal-appearing macrophages and only mild stimulus of the thymocytes. Peak heights of radioactivity indicating the numbers of T-cell responders were usually between 7 and 10 fold higher than baseline.
  • L. casei subspecies rhamonosus ATCC 7469, was grown overnight in 20 ml of MRS broth to a concentration of 3.6 ⁇ 10 9 CFU/ml, washed and pelleted as described above. The pellet was suspended in saline to provide the ratios to monocytes as shown in Table 3 below.
  • LPS lipopolysaccharide
  • IL-1 IL-1
  • Bacteria were grown as described in Examples 1 and 3 and combined as pairs of commensals. In combination, they were immediately admixed with macrophages and added to the monocytes or macrophages as shown below. Peak heights were between 1.5 and 3 fold higher than baseline. The results are shown in Table 5.
  • the macrophage is protected against a pathophysiological response to a dose of E. coli or LPS by the presence of another commensal bacterium; i.e., the appearance of the macrophage exposed to E. coli or to LPS is different than when exposed to E. coli or LPS in the presence of a commensal.
  • the presence of the commensal population does not alter the degree of activation of the macrophages, but rather alters the cytokine response as seen by morphological changes typical of a balanced response. Radioactive peak heights were 2 to 10 fold above baselines. The results are shown in Table 6.
  • the macrophage is protected against a pathophysiological response to a dose of E. coli or LPS by the presence of other commensal bacteria; i.e. the appearance of the macrophage exposed to E. coli or to LPS is different than when exposed to E. coli or LPS in the presence of commensals.
  • the presence of the commensal population does not dramatically alter the activation of the macrophages, but rather alters the cytokine response as seen by morphological changes typical of a balanced response.
  • the results are shown in Table 7. Radioactive peak heights were 2 to 9 fold above baselines.

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Abstract

L'invention concerne des procédés et des compositions de stimulation du système immunitaire d'un animal par l'administration de bactéries apathogènes choisies dans la famille de lactobacilliacea en un rapport d'environ 500:1 et 1:500 de bactéries/macrophage, le macrophage étant présent dans la cavité oro-pharyngée-alvéolaire de l'animal, dans un excipient acceptable capable d'acheminer lesdites bactéries dans ladite cavité oro-pharyngée-alvéolaire de l'animal. Lesdits procédés et compositions sont particulièrement utiles pour moduler les réponses de macrophages chez l'animal au E. coli et à d'autres germes pathogènes, et réduire le risque de choc septique dû à l'exposition à ces germes pathogènes.
PCT/US1994/005414 1993-05-11 1994-05-11 Procede de stimulation et de modulation du systeme immunitaire d'animaux a l'aide de compositions microbiennes Ceased WO1994026114A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026732A1 (fr) * 1995-02-28 1996-09-06 Newpharma S.R.L. Compositions de bacteries lactiques et de lysats de saccharomyces et leur utilisation therapeutique
KR100406344B1 (ko) * 1997-08-21 2003-11-19 뉴질랜드 대어리 보오드 면역을 향상시키는 젖산균

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4347240A (en) * 1979-02-27 1982-08-31 Kabushiki Kaisha Yakult Honsha Antitumor agent containing Lactobacillus casei YIT 9018

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4347240A (en) * 1979-02-27 1982-08-31 Kabushiki Kaisha Yakult Honsha Antitumor agent containing Lactobacillus casei YIT 9018

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
IMMUNOLOGY, Volume 63, issued 1988, PERDIGON et al., "Systemic Augmentation of the Immune Response in Mice by Feeding Fermented Milks with Lactobacillus Casei and Lactobacillus Acidophilus", pages 17-23. *
INFECTION AND IMMUNITY, Volume 53, Number 2, issued August 1986, PERDIGON et al., "Effect of Perorally Administered Lactobacilli on Macrophage Activation in Mice", pages 404-410. *
INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY, Volume 14, Number 2, issued February 1992, KINOSHITA et al., "Oral Administration of a Streptococcal Agent OK-432 Activates Alveolar Macrophages in Mice", pages 205-211. *
JOURNAL OF FOOD PROTECTION, Volume 49, Number 12, issued December 1986, PERDIGON et al., "Effect of a Mixture of Lactobacillus Casei and Lactobacillus Acidophilus Administered Orally on the Immune System in Mice", pages 986-989. *
JOURNAL OF FOOD PROTECTION, Volume 53, Number 5, issued May 1990, PERDIGON et al., "The Oral Administration of Lactic Acid Bacteria Increase the Mucosal Intestinal Immunity in Response to Entereopathogens", pages 404-410. *
JOURNAL OF INDUSTRIAL MICROBIOLOGY, Volume 6, issued 1990, MITSUOKA, "Bifidobacteria and their Role in Human Health", pages 263-268. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026732A1 (fr) * 1995-02-28 1996-09-06 Newpharma S.R.L. Compositions de bacteries lactiques et de lysats de saccharomyces et leur utilisation therapeutique
KR100406344B1 (ko) * 1997-08-21 2003-11-19 뉴질랜드 대어리 보오드 면역을 향상시키는 젖산균

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