Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-11-15
2003-01-14
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S234100, C424S184100, C424S245100, C424S282100, C424S009200, C424S439000
Reexamination Certificate
active
06506388
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a decomposition product of bacterial cell walls, an immunomodulator, consisting of bacterial cells or their decomposition materials which can suppress selectively IgE antibody production, and to provide their production methods and foods containing them.
RELATED ART
Immediate type allergies or atopies, such as pollen allergy, asthma, atopic dermatitis, food allergy, are known to be mediated by antibody of IgE isotype immunoglobulin. Symptoms of atopy are elicited when the IgE antibodies react to antigen, resulting in release of various physiologically active substances such as histamine, serotonin, leucotrienes and others.
For the prevention and treatment of immediate type allergies, drugs generally used today are those which are antagonistic to the mediators, for instance, antihistaminics, drugs which inhibit release of mediates from mast cells, and corticosteroids which inhibit activation of various immunocytes resulting in inhibition of cytokine production.
Since the antibody which mediates an immediate allergy is an IgE antibody, an agent which suppress IgE antibody production can be thought to be effective for the treatment of immediate type allergies. However, there are no effective drugs which suppress only IgE isotype antibody without suppressing other isotypes such as IgG, IgA so on,which are important for body defense mechanisms to various infectious diseases.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide an immunomodulator having suppressive activity on IgE production without any suppressive effect on other isotypes of antibody.
As a result of extensive investigation in order to solve the above-mentioned problem, the present investigators have unexpectedly found firstly that bacterial cells of Corynebacterium, Brevibacterium, and Microbacterium species, and mutant strains derived from the species are able to suppress selectively IgE type antibody production by oral administration of these bacterial cells without any suppressive effect on the production of other isotypes, even if enhancing these antibody production, and secondly that a decomposition product of above mentioned bacteria by enzymatic treatment and such, has more potent immunomodulative activity than that of the bacterial cells by themselves. These findings have led to the completion of the present invention.
That is, the present invention is to provide an immunomodulator, an immunomodulator food, immunomodulator drink containing bacterial cells belonging to Corynebacterium, Brevibacterium, and Microbacterium species, and mutant strains derived from the species, and a decomposition material of the above mentioned bacteria by enzymatic treatment and such.
The invention provides a method of modulating the immunological function by administering orally a pharmacologically effective amount of bacterial cells or their decomposition materials to a human being.
The invention provides a bacterial cell wall decomposition product (or decomposition material) having an immunomodulative activity, which is produced by dissolving the cell wall of at least one selected from the group consisting of bacteria belonging to Corynebacterium genera, Brevibacterium genera and Microbacterium genera and mutant strains of these bacteria.
The invention provides a process for manufacturing the above-shown bacterial cell wall decomposition product, which comprises dissolving the cell wall of at least one selected from the group consisting of bacteria belonging to Corynebacterium genera, Brevibacterium genera and Microbacterium genera and mutant strains of these bacteria.
It is preferable to the process to dissolve the cell walls with one of glucosidase and endopeptidase in the medium of an isotonic solution, separate the protoplast generated by the enzymatic digestion of the bacterial cells from the medium, and furthermore enzymatically treat the dissolved material of the bacterial cells with the other of the endopeptidase and glucosidase.
It is preferable to dissolve the cell walls with one of glucosidase and endopeptidase in the medium of an isotonic solution (biological saline), centrifuge the solution to obtain the supernatant and enzymatically treat the supernatant with the other of the endopeptidase and glucosidase.
The decomposition production of the invention may be obtained when at least 30% or 29% of the bacterial cells have been decomposed. This decomposition extent can be observed in terms of determination of dissolved hexosamine or glucosamine, which is present in the supernatant. Alternatively, it can be observed in terms of optical density of the bacterial suspension. The invention may reach at least 25% of optical density.
The invention provides an immunomodulator food or drink containing the bacterial cell wall decomposition product of the invention.
The invention provides a method of treating or preventing allergy, which comprises administering a pharmacologically effective amount of the decomposition product of the invention to a person suffering from allergy, and use of the decomposition product for manufacturing immunomodulator.
The invention relates to use of bacteria belonging to Corynebacterium genera, Brevibacterium genera and Microbacterium genera and mutant strains of these bacteria. That is, the invention provides a method of treating or preventing allergy, which comprises administering a pharmacologically effective amount of the bacteria to a person suffering from allergy; use of the bacteria for manufacturing immunomodulator; an Immunomodulator food or drink containing the bacteria; and a method of effecting immunomodulation, which comprises administering a pharmacologically effective amount of the bacteria to a person suffering from immunodeficiency.
It is preferred to the production of the decomposition product that the bacterial cell wall is digested with glucosidase and/or endopeptidase; a bacterium of Corynebacterium genus is
Corynebacterium glutamicum
or
Corynebacterium herculis
; a bacterium of Brevibacterium genus is
Brevibacterium flavum
; a bacterium of Microbacterium genus is
Microbacterium ammoniaphilum
; the glycosidase is egg white lysozyme or N-acetylmuramidase SG; the decomposition is performed by induction of lysogenic bacteriophage; the decomposition is performed by autolysis; the endopeptidase is bromelain; or the endopeptidase is one selected from the group consisting of seratiopeptidase, protease produced by Streptomyces griseus (K-1 strain), protease produced by Bacillus subtilis, Seaproze S produced by
Armillaria mellea
(Naratake in Japanese), trypsin, Achromobacter protease I and
Grifola frondosa
(Maitake in Japanese) metaloendopeptidase.
It is preferable that the immunomodulative bacterial cells are products produced by culturing cells of strains belonging to Corynebacterium, Brevibacterium, and Microbacterium species, and mutant strains derived from the species, heating the culture to kill the cells, harvesting the killed cells and dried. As for products of immunomodulative decomposition materials made of the above-mentioned bacteria, cultured cells are decomposed by autolysis, induction of lysogenic bacteriophage, and enzymatic treatment using cell wall digesting enzymes.
In the invention, decomposition material is defined by a generation of soluble hexosamine of at least 30% of the total bacterial hexosamine.
DETAILED DESCRIPTION OF THE INVENTION
An immuno-adjuvant is called for as the substances which enhances antibody formation by injecting them mixed with an antigen to animals. Killed bacterial cells of
Mycobacterium tuberculosis
have been known to have immuno-adjuvant activity. Results of study for clarifying an effective component of the adjuvant activity revealed that the smallest component was muramyl-L-alanyl-D-isoglutamine (MDP), a component of peptidoglycan of bacterial cell wall. The existence of MDP is also known in all the bacterial cells other than bacteria of
Mycobacterium tuberculosis
, including pathogenic and also non-pathogenic bacteria, irrespective
Iwashita Sadaichi
Shionoya Hiroshi
Yajima Mizuo
Asama Chemical Co., Ltd.
Devi S.
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