Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
1999-02-03
2001-11-13
Clark, Deborah J. R. (Department: 1633)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C800S008000, C800S011000
Reexamination Certificate
active
06316691
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an atrichia mouse and more particularly to a novel atrichia mouse capable of growing juvenile hair but deficient in the ability to grow pelage hair.
BACKGROUND ART
As the animals in routine use in studies on therapeutic drugs for dermatitis, among other diseases, the mouse, rat, and rabbit can be mentioned. However, there is the disadvantage that in order that those animals may be actually used in such studies, they must be subjected to various pretreatments. In a screening for antiallergic drugs, for instance, animals which have undergone PCA (passive cutaneous anaphylaxis) reaction are used as is well known. However, to induce this PCA reaction in animals, an antiserum containing a homologous or heterologous tissue reagin must be administered to denuded animals and for quantification of this reaction, an antigen and a dye or radiolabeled albumin must be administered intravenously after a certain interval of time (48-168 hours when the homologous PCA IgE antibody was used). (Hiroichi Nagai: 2-1 Dermatitis (1) PCA Reaction, Seibutsu-Yaku-Kagaku Jikken Koza (Biopharmaceutical Science Experiment Series) Vol. 12, Inflammation and Allergy (I-1) (ed. Kazuo Ohuchi), Hirokawa Shoten, Tokyo, 1993, p.96-109). The foregoing means not only the absolute need for such pretreatment procedures but also the risk for the experimenter being exposed to the antiserum and other factors which might adversely affect his or her health. Therefore, development of an animal model of disease, which might be submitted to studies on therapeutic drugs, such as drugs for dermatitis, without said or other pretreatments, has been awaited.
The object of the present invention, therefore, is to provide an animal model of disease meeting the above demand.
During, intensive investigations, the inventors succeeded in producing an atrichia mouse suited for the object. The present invention is based on the above results.
DISCLOSURE OF THE INVENTION
The present invention relates to an atrichia mouse comprising having the ability to grow juvenile hair but being deficient in the ability to grow pelage hair and more particularly to such an atrichia mouse showing a 70% or higher spontaneous prevalence of wet (ulcerative) and dry skin lesions at and after the 24th week of age, such an atrichia mouse in which the number of mast cells in the skin is not less than about 50 cells/linear mm at the 24th week of age, and such an atrichia mouse in which the serum immunoglobin E (IgE) level is not less than about 3500 ng/ml at the 24th week of age.
As mentioned above, the atrichia mouse of the invention is characterized by the ability to grow juvenile hair but the inability to grow pelage hair. Mice with such a deficiency in pelage hair-growing ability have not been established, or even reported, to this day.
Furthermore, the atrichia mouse of the invention is characterized in that the spontaneous prevalence of wet and dry skin lesions is not less than 70% at and after the 24th week of age, that the number of mast cells in the skin is not less than about 50 cells/linear mm at the 24th week of age, and that the serum IgE level is not less than about 3500 ng/ml at the 24th week of age.
Meanwhile, the ordinary hair mouse does not spontaneously develop wet or dry skin lesions and its number of mast cells in the skin is usually about 10 cells/linear mm according to the data generated by the present inventors. With regard to the serum IgE level, it is usually very low although few quantitative determinations have been reported and no normal level has been postulated. Incidentally, according to the determination by the present inventors (using, the test kit described hereinafter), the IgE level was 0.0-137.5 ng/ml in ICR mice at the 16
th
week of age and 0.0-5.0 ng,/ml in ddY mice at the 16
th
week of age as shown hereinafter ill Tables 3 and 4. As reported in the literature, the IgE level in normal mice is <20-608 ng/ml in BALB/c mice and <20 ng/ml in all C3H mice and the level in animals experimentally infected with a parasite (
Nipopostronoylus brasiliensis
) is 2240-7168 ng/ml in BALB/c mice and 1365-3068 ng/ml in C3H mice (Takao Hirano & Hiroaki Miyajima: Characterizations and applications of rat monoclonal murine IgE antibody, Medical Immunology, 15(2), 211-216 (1988)).
Furthermore, even the existing hairless mice do not develop wet or dry skin lesions spontaneously and their number of mast cells in the skin calculated by the present inventors is generally about 20 cells/linear mm. With regard to the serum IgE level, the level found by the present inventors (using the test kit described hereinafter) was 102.0-253.0 ng/ml in HRS/J mice at the 20th week of age as shown hereinafter in Table 2.
In contrast, the atrichia mouse of the invention is characterized by an exceptionally high prevalence of spontaneous skin lesions, a high number of mast cells in the skin, and a high serum IgE level at (or after) the 24th week of age as mentioned above and, in those aspects, distinctly different from any of the ordinary hairy mouse and existing hairless mice, thus substantiating its novelty.
On the strength of the above characteristics, the atrichia mouse of the invention is of great use in the screening for prophylactic and therapeutic drugs for dermatitis and as an animal model of disease for experiments for efficacy evaluation and other purposes.
Furthermore, even prior to the 24
th
week of age, the atrichia mouse of the invention presents a steady hairless condition as compared with the existing hairless mice and denuded mice and therefore, offers the advantage that individuals without development of skin lesions (particularly animals of low age) can be used without requiring the trouble of hair clipping as experimental animals for the dermal irritation study of drugs to be administered transdermally, inclusive of medicines and cosmetics.
The present invention, therefore, further provides a method of testing the efficacy and/or dermal irritation potential of drugs to be applied to the skin, such as medicinal and cosmetic preparations, typically prophylactic and therapeutic drugs for dermatitis, by using the above atrichia mouse of the invention.
The above-mentioned test according to the invention can be carried out in the same manner as the routine tests of the kind except that the use of the atrichia mouse of the invention is an essential requisite. For example, a typical test procedure comprises applying a test substance in a dosage form suited to transdermal administration, such as an ointment or a plaster, and in a suitable dose to the skin of the atrichia mouse of the invention in the conventional manner and monitoring with the passage of time of its action and effect in accordance with the ordinary observation and evaluation protocol.
The atrichia mouse of the invention is originated from a sparsely coated mutant (male) which was accidentally discovered in the process of brother-sister breeding, of the hybrid mice between a female C3H/He mouse and a male ddY mouse. When the above-mentioned sparsely coated mouse was subjected to brother-sister mating with a female mouse of the littermate, only male sparsely coated animals were obtained up to the subsequent second generation but male and female sparsely coated animals were obtained in the third generation. By subjecting those male and female sparsely coated animals to brother-sister mating, the female atrichia animal of the invention was obtained, and by subjecting this female atrichia animal to brother-sister mating with a male sparsely coated animal of the littermate, male and female atrichia animals could be obtained. Using those male and female atrichia animals as the atrichia F
0
on, they were subjected to brother-sister mating, whereupon all the offspring became atrichia animals. In this manner, the atrichia mouse of the invention was successfully fixed and established. The atrichia mouse of the invention will hereinafter be referred to as the Naruto Research Institute Otsuka Atrichia (hereinafter, “NOA”) mouse.
The method o
Kondo Taizo
Kondo Toshio
Shiomoto Yasuhisa
Clark Deborah J. R.
Kerr Janet M
Otsuka Pharmaceutical Factory Inc.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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