WO2002074077A1 - Souris presentant un modele d'une maladie de la peau, alimentation pour creer ces souris et procede pour evaluer la substance de test en utilisant ces souris - Google Patents

Souris presentant un modele d'une maladie de la peau, alimentation pour creer ces souris et procede pour evaluer la substance de test en utilisant ces souris Download PDF

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Publication number
WO2002074077A1
WO2002074077A1 PCT/JP2002/002465 JP0202465W WO02074077A1 WO 2002074077 A1 WO2002074077 A1 WO 2002074077A1 JP 0202465 W JP0202465 W JP 0202465W WO 02074077 A1 WO02074077 A1 WO 02074077A1
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WIPO (PCT)
Prior art keywords
feed
mouse
skin
disease
mass
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PCT/JP2002/002465
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English (en)
Japanese (ja)
Inventor
Hiroaki Eiro
Masato Kuramoto
Masayuki Hoshino
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Shiseido Company, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Shiseido Company, Ltd. filed Critical Shiseido Company, Ltd.
Publication of WO2002074077A1 publication Critical patent/WO2002074077A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/50—Feeding-stuffs specially adapted for particular animals for rodents

Definitions

  • the present invention relates to a model animal, and more specifically to, for example, a skin disease model mouse, and a means and use for producing the same.
  • Disease model animals or disease model animals have generally been established to utilize abnormal traits similar to human diseases of a certain animal strain for the purpose of investigating the causes of human diseases and establishing treatments.
  • Such a pathological model is an experimental onset model in which a normal animal is artificially manipulated to create a disease state or symptom similar to a human disease, and a spontaneous onset model in which a pathological state is spontaneously developed as a genetically fixed trait.
  • Exists. are primarily aimed at developing treatments for intractable diseases.
  • a variety of skin disease models have been proposed, including atopic dermatitis, which is considered an intractable or intractable disease. These are mainly experimental onset models in which animals are sensitized with specific drugs to create models from the viewpoint of onset in the skin.
  • a typical example is a model in which dermatitis was induced using papten in SPF (Specific Pathogen Free: no specific microorganisms and no parasites) animals of NCZN ga mice established as inbred strains (No. 125 Japanese Society of Veterinary Science, F 1-12), a model in which NCZNga mice were bred in a conventional environment and spontaneously developed pruritic dermatitis (CR J LETTERS Vol. 11, No.
  • the disease does not develop unless hapten induction (administration of picryl chloride) is performed for a long period of time.
  • hapten induction administration of picryl chloride
  • the breeding environment is low, there is a risk of infectious disease due to the low microbiological grade of the breeding environment. Therefore, it is not always satisfactory as a model animal for evaluating a test substance by administering it to the skin.
  • the incidence is estimated to be about 70 to 80% at the maximum.
  • An object of the present invention is to provide a model animal that is easier to handle as an experimental animal and that more closely resembles the pathology of human skin diseases.
  • skin diseases involve multiple factors, such as genetic and environmental factors.
  • the present inventors have searched for a model animal in which a skin disease easily develops, which is a system in which both factors are combined.
  • atopic skin disease or dry skin
  • cystic skin disease can be stably induced. It was found that switching from feed breeding to normal feed breeding reduced the symptoms in about one week.
  • mice with such dermatological disorders have significantly increased IgE antibodies, which are considered to be the largest factors involved in the development and progression of atopic dermatitis, allergic rhinitis and bronchial asthma. Was also found.
  • these diseases can be induced not only at a rate of substantially 100%, but also progressively or alleviate the symptoms at will.
  • the present invention provides a model mouse for a skin disease and / or a disease associated with an abnormality in an immune index, which is derived from a mouse having a hairless and thymic phenotype.
  • the hairless and thymus-existing phenotype of a mouse has a magnesium content, preferably a zinc content, among minerals in a normal feed for rodents after weaning. Under normal mouse rearing conditions except feeding a significantly reduced special diet, the mice should be reared for a period of time sufficient to induce skin disease and / or disease associated with abnormalities of immune indicators.
  • the present invention also provides a method for producing the model mouse, characterized by
  • the test substance can be used for preventing or preventing a skin disease and / or a disease associated with abnormal immune indicators. It also provides a method for evaluating whether or not it has a therapeutic effect.
  • FIG. 1 is a graph showing the change in body weight when a normal feed and a special feed (prescription 1) are fed.
  • ⁇ is based on the data of the male normal feed group
  • ⁇ is based on the data of the male special diet group
  • ⁇ is based on the data of the female normal feed group
  • ⁇ is based on the data of the female special feed group.
  • FIG. 2 is a graph showing the change in body weight when a normal feed and a special feed (prescription 2) are fed.
  • ⁇ , ⁇ , Qin and ⁇ in the graph have the same meanings as in Fig. 1, respectively.
  • FIG. 3 is a photograph instead of a drawing showing the condition of the back skin of mice after each feed.
  • (a) is a photograph of a normal feed (four weeks after feeding)
  • (b) is a photograph of a special diet (four weeks after feeding).
  • FIG. 4 is a histological photograph replacing the drawing of mouse skin tissue after each feed.
  • (a) and (b) are HE-stained skin tissues of the animals after breeding in the same manner as in FIG. 3, and are 400 times enlarged photographs.
  • FIG. 5 is a graph showing the skin moisture content on the back of the mouse after feeding each feed (special feed is prescription 1).
  • A is a special feed group and B is a normal feed group.
  • FIG. 6 is a graph showing the skin moisture content on the back of the mouse after feeding each feed (special feed is prescription 2).
  • A is a special feed group and B is a normal feed group.
  • FIG. 7 is a graph showing the transepidermal water loss per unit area of mouse skin after feeding each feed (special feed is prescription 1).
  • A is a special feed group and B is a normal feed group.
  • FIG. 8 is a graph showing the transepidermal water loss per unit area of mouse skin after feeding each feed (special feed is prescription 2).
  • A is a special feed group and B is a normal feed group.
  • “Hairless and having a thymic phenotype” means that the trait described is not caused by invasive (eg, surgical, etc.) means and the native gene is Means to appear in cells or individuals by the action of Therefore, “hairless” excludes hairlessness due to shaving or artificial hair removal.
  • Skin disease does not necessarily mean a serious skin disease, but refers to a condition in which the function, structure, or both, of the skin is impaired. For example, these conditions include a significant decrease in skin moisture with impaired skin barrier function or structure, a significant increase in transepidermal water loss (dry skin), a significant increase in skin thickness, There are conditions such as hypertrophy, abnormal keratinization, and intracellular edema in basal cells. “Significantly” refers to control mice (mouse with a hairless and thymic phenotype bred under normal breeding conditions, mice that correspond to a model mouse with and without skin disease induction). It means the degree of statistically significant difference when compared.
  • an "immune index” is a component within an individual that reflects the immune status of the animal in question, and typically includes immunoglobulin E (IgE) as a typical one.
  • IgE immunoglobulin E
  • the blood IgE concentration is significantly increased. It is known that IgE is generally significantly increased in atopic patients.
  • the disease of the model mouse according to the present invention is mild to severe atopy uniform disease (atopy-like dry skin and This is very similar to the expression of cysteine-like skin), and it can be understood that it is useful as a model animal.
  • the magnesium content in the feed diet is the same except that, in some cases, the zinc content is also different.
  • the growth status during breeding eg, changes in body weight
  • major organs such as brain, heart, lung, kidney, and spleen, and hematological properties and hematologic properties except for IgE concentration are bred between the model mouse and the control mouse according to the present invention. Does not show a significant difference.
  • the model mouse according to the present invention is a very useful model animal that selectively shows skin diseases and changes in IgE concentration.
  • Such a model mouse according to the present invention is provided as an invention of another aspect. It can be easily obtained by the method of preparing a model mouse.
  • a mouse having a hairless and thymic phenotype is used.
  • the above-described model mouse according to the present invention can be induced.
  • Skn HR-1 strain (albino strain) donated by Dr. Don Forbes of Temple University Skin and Cancer Hospital (Philadelphia, USA) is converted into SPF, and Use a hairless and thymic phenotype that has been selected as a good breeder from the inbred lines.
  • the Skn: HR-1 line described above is a line established at Temple University through the cross between a hairless mouse of unknown origin and an inbred CBAZMan mouse. Following this, one of skill in the art could use other available hairless mice to establish a mouse line with a hairless and thymic phenotype that can be used in the present invention.
  • the mouse having the phenotype used in the examples of the present invention can be obtained, for example, as a HR-1 hairless mouse from Hoshino Experimental Animal Breeding Laboratory, located in Hachijo, Yashio, Saitama, Japan. is there.
  • mice having such a phenotype are bred on a special diet in which the magnesium content is significantly reduced among the minerals in the normal breeding diet for rodents (eg, mice, rats, nomsters).
  • the normal breeding feed generally contains at least crude protein, for example, about 16 to about 30%, and crude fat, for breeding or breeding experimental mice, rats, and hamsters.
  • crude protein for example, about 16 to about 30%
  • crude fat for breeding or breeding experimental mice, rats, and hamsters.
  • crude fiber for example, about 2 to about 17%
  • crude ash for example, about 5 to about 10%
  • vitamin-based for example, about 0.2 to about 0.5%
  • minerals for example, from about 0.18 to about 0.40%
  • mineral magnesium is converted to elements per total feed mass, for example, from about 0.24 to 0.26.
  • zinc is contained in an amount of about 0.006 to 0.007% by mass, based on the total feed mass in terms of element.
  • the composition of such a normally fed diet may be known from the pamphlets of manufacturers of various laboratory animal feeds. For example, a standard feed ingredient list distributed by Oriental Yeast Co., Ltd. can be used.
  • the special feed that can be used in the method for producing a model mouse of the present invention is a mineral feed in the above-mentioned normal breeding feed, which contains a significant amount of magnesium and, in some cases, zinc. It is reduced to: A significant reduction means that the magnesium content is about 0.1% by mass or less, preferably 0.05% by mass or less, more preferably 0.01% to 0.02% by mass, based on the total feed mass. Further, when the zinc is reduced, the zinc content is about 0.0055% by mass or less, preferably about 0.006% to 0.0055% by mass, based on the total feed mass.
  • a mouse having a hairless and thymic phenotype is bred to the mouse for a period of time sufficient to induce a skin disease and a disease associated with abnormalities of Z or immune index.
  • the time to start feeding the animals with special feed is not limited in principle, but in general, the onset of skin disease tends to be accelerated when it is started immediately after weaning (3 to 4 weeks of age). .
  • the symptoms of the above-mentioned skin diseases gradually appear in the second to fourth weeks (at the age of 5 to 8 weeks) from the start of feeding, and / or the IgE concentration becomes lower. It rises significantly.
  • the feeding of special diet is stopped and the feeding of normal feed is continued instead, the symptoms will be reduced in about one week. Feeding should be carried out with the animals allowed free access to feed.
  • breeding conditions are based on “Architecture and Equipment of Laboratory Animal Facility” (1996 Guideline, Architectural Institute of Japan).
  • the temperature is 21-25 ° (, the humidity is 40-70%, the ventilation frequency is 10-15 times, Z time, the lighting time is 12 hours, and the breeding equipment is synthetic.
  • Resin flat-bottomed cages (single: 136: 208x115 mm, group: 225x338x140 mm), drinking water is free to use UV water and microfiltered tap water, dust is class 10 , 000 or less (area where no animals are bred), 3 or less falling bacteria (area where no animals are bred), odor is less than 2 Oppm in ammonia concentration, and illuminance is 150-300 lux (40-85cm on the floor) ), The breeding was conducted in a breeding environment with noise of 60 dB or less.
  • the present invention provides the above-mentioned special feed as a further aspect of the invention.
  • the special feed is used for producing a model mouse according to the present invention.
  • the model mouse according to the present invention or the method for producing It can be used to assess whether the degree of skin disease and disease associated with abnormal z or immune indicators can be altered (eg, prevention or treatment).
  • This evaluation is useful, for example, for evaluating whether dermatological preparations and cosmetics or the specific components contained therein have the intended effect, and for screening substances having such an effect.
  • the test substance is orally or parenterally or dermally administered to the model mouse in which the disease has been induced at any time, and after feeding the special diet, Obtain data for evaluation by tracing changes in the condition of the patient.
  • the test substance when the method for producing a model mouse is used to evaluate a test substance, the test substance is administered to the animal by the above-mentioned administration route before or during feeding of the special diet to induce disease.
  • the efficacy of the test substance can be evaluated by tracing whether it is suppressed or prevented.
  • the targets of the above-mentioned trace are, for example, skin moisture, transdermal water loss, skin thickness, and blood IgE concentration, which will be described later, but are not limited thereto.
  • HR-1 hairless mice purchased from the Hoshino Test Animal Breeding Center
  • HR-1 hairless mice purchased from the Hoshino Test Animal Breeding Center
  • Equipment (1996 Edition Guidelines, Architectural Institute of Japan). Normally, 4-6 g / animal are fed daily.
  • Vitamin-based1 4.5
  • V.A (750,000 IUZg) 0.9528 V.D 3 (500,000 IU / g) 0.2133 V.E (50% W / W) 7.1104 V.K 3 0.1778
  • the HR-1 hairless mice were divided into a normal breeding feed group and a special breeding group.
  • the normal breeding group consisted of a normal breeding feed (mouse feed CRF-1: manufactured by Oriental Yeast Co., Ltd.) and a special breeding group.
  • the animals were fed a special diet (low Mg diet) freely and bred in accordance with “Construction and Equipment of Experimental Animal Facility” (1996 Guideline, edited by the Architectural Institute of Japan), and conducted the following tests.
  • mice were weighed every week for 6 weeks from the start of feeding, and the changes were compared by sex. The results are shown in Figure 1 (for formulation 1) and Figure 2 (for formulation 2).
  • Normal feed group special feed group (Formulation 1 and Formula 2) (both 5 males); 5 weeks old at the start of feeding
  • Skin water content Skin conductance was measured using Sukicon 200 (manufactured by IBS Japan) and used as an index of skin water content. The results are shown in FIG. 5 (for formulation 1) and FIG. 6 (for formulation 2).
  • Transepidermal water loss The transepidermal water loss per unit area was measured using Tevameter TM TM 210 (Courage + Khazaka). The results are shown in Figure 7 (for formulation 1) and Figure 8 (for formulation 2).
  • Skin thickness was measured using a dial thickness gauge. The results are shown below in Table 1 (for Formula 1) and Table 2 (for Formula 2). Table 1 Skin thickness group Number of animals
  • the figures are mean figures SD 1 gE concentration in blood Sex group Number of animals Blood-t 1 gE concentration
  • IgE concentration In the special diet (Formulation 1 and Formula 2) group, IgE concentration tended to increase significantly in both males and females (P ⁇ 0.001).
  • This example confirms that a steroid drug known to be effective for the treatment of a skin disease is also effective for the skin disease of the model mouse of the present invention, and that the model mouse can be used as a skin disease model Provided for illustrative purposes.
  • HR-1 mice Male
  • 4 weeks old were used as animals, fed the above-mentioned special diet (formulation 1) for 5 weeks, and drug application experiments were started at the age of 9 weeks.
  • the following three groups were observed with 10 animals in each group.
  • Group 1 Drug administration group (special feed (prescription 1) fed for the entire period + drug administration)
  • Rinderon-I VG cream 12% in lg, betamethasone valerate 1.2 mg, gentamicin sulfate lmg titer; Shionogi Pharmaceutical Co., Ltd. 0.01 g 5 times all over the back skin Z weeks (1 time Z 1 was applied at a frequency of
  • Group 2 Special feed administration group (Special feed is fed for the entire period only)
  • the model mouse or the method for producing the same according to the present invention can be used to evaluate whether or not a test substance can change (eg, prevent or treat) a skin disease and / or a disease associated with an abnormality in an immune index. .
  • This evaluation is useful, for example, for evaluating whether dermatological preparations and cosmetics or the specific components contained therein have the intended effect, and for screening substances having such an effect. waxes c
  • making industry and feed industry experimental animals also available in industry for evaluation and testing of the active ingredient for use in dermatological or cosmetic.

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Abstract

L'invention concerne des souris modèles pour étudier des maladies de la peau et/ou des maladies associées à des anomalies de l'indice d'immunité, qui présentent des phénotypes sans poils ou thymiques. L'invention concerne aussi un procédé pour créer ces souris en leur donnant une nourriture à faible teneur en magnésium (éventuellement avec une faible teneur en zinc), et cette alimentation.
PCT/JP2002/002465 2001-03-16 2002-03-15 Souris presentant un modele d'une maladie de la peau, alimentation pour creer ces souris et procede pour evaluer la substance de test en utilisant ces souris WO2002074077A1 (fr)

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JP2001076113 2001-03-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102835605A (zh) * 2012-09-24 2012-12-26 吴江市田宇生物科技有限公司 一种实验小鼠饲料添加剂
CN104170797A (zh) * 2014-08-26 2014-12-03 扬州大学 大白猪一般抗病力综合选择指数选择育种方法
CN111528348A (zh) * 2020-06-02 2020-08-14 北京金道欣生物技术有限公司 一种实验鼠饲料配方

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102835605A (zh) * 2012-09-24 2012-12-26 吴江市田宇生物科技有限公司 一种实验小鼠饲料添加剂
CN104170797A (zh) * 2014-08-26 2014-12-03 扬州大学 大白猪一般抗病力综合选择指数选择育种方法
CN104170797B (zh) * 2014-08-26 2016-08-03 扬州大学 大白猪一般抗病力综合选择指数选择育种方法
CN111528348A (zh) * 2020-06-02 2020-08-14 北京金道欣生物技术有限公司 一种实验鼠饲料配方

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