WO2004039149A1 - ギラン・バレー症候群及び/又はフィッシャー症候群発症モデル非ヒト動物 - Google Patents
ギラン・バレー症候群及び/又はフィッシャー症候群発症モデル非ヒト動物 Download PDFInfo
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- WO2004039149A1 WO2004039149A1 PCT/JP2003/013958 JP0313958W WO2004039149A1 WO 2004039149 A1 WO2004039149 A1 WO 2004039149A1 JP 0313958 W JP0313958 W JP 0313958W WO 2004039149 A1 WO2004039149 A1 WO 2004039149A1
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- guillain
- syndrome
- human animal
- barre
- barre syndrome
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- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/027—New breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0276—Knockout animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
- A01K2267/0318—Animal model for neurodegenerative disease, e.g. non- Alzheimer's
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
Definitions
- the present invention relates to a model non-human animal exhibiting Guillain-Barre syndrome (Fisher syndrome).
- Guillain-Nole syndrome which can be obtained by immunizing a ganglioside GQ1b to a non-human animal lacking the function of the FcaRIIB gene on the chromosome (nonhuman animal lacking the FcaRIIB gene).
- the present invention relates to an onset model non-human animal, and a method for screening for a therapeutic agent for Guillain-Barre syndrome using the model non-human animal.
- GRS Guillain-Barre syndrome
- the Guillain-Barré syndrome develops 1 to 2 weeks after the appearance of cold-like symptoms and rapidly progresses to flaccid motor paralysis (limb weakness in the extremities) It is an inflammatory demyelinating disease in the peripheral nerve characterized by deep tendon reflex loss, dysphagia, dysarthria, deep sensory disorders, and autonomic nervous symptoms (arrhythmia, fluctuations in blood pressure).
- the Guillain-Barré syndrome develops in two out of 100,000 people annually, and it is said that about 2000 to 250 new cases are affected every year in Japan.
- Gandarioside is classified into GM1, GM2, GD1a, GDIb, GTla, GQlb, etc. based on its molecular structure.
- autoantibodies corresponding to each are detected in patient sera.
- anti-GM1 antibody and anti-GD1a antibody appear as anti-gandarioside antibodies in serum.
- anti-GQ1b antibodies are specifically elevated in almost all cases of serum in acute phase of Guillain-Barre syndrome with ophthalmoplegia and Fisher syndrome.
- Guillain-Barre syndrome is associated with Campylobacter jejuni, one of the causative bacteria of food poisoning.
- Fisher syndrome is known as a subtype of Guillain-Barré syndrome. It is said that Fisher's syndrome accounts for about 5% of Guillain-Barre syndrome, It develops as a line infection, causing extraocular muscle paralysis, diplopia, ataxia, loss of tendon reflexes, and facial paralysis. It has the same symptoms as Guillain-Barre syndrome, but does not cause limb paralysis in humans.
- Fischer syndrome group an increase in blood IgG antibody titer against gandarioside GQ1b has been reported.However, as in the above-mentioned Guillain-Barre syndrome, the mechanism of its onset has not been elucidated. However, no therapeutic drug has been developed.
- FcR receptor that recognizes and binds the Fc portion of Ig
- FcrR body fluids
- Fc receptor Fc receptor
- a receptor protein that specifically binds to the r-chain is based on similarity in gene structure, and is based on type I (CD64 antigen) and type II (CD32 antigen). ), Type III (CD16 antigen).
- F cr RII unlike other F c Rs, has low affinity for monomeric IgG and binds to multivalent IgG that has become an immune complex, resulting in monocytes, macrophages, It is widely expressed on hematopoietic stem cells, including polymorphonuclear leukocytes (PMN;), mast cells, platelets, some T cell lymphocytes, and some B cell lymphocytes.
- Fc7RII has three types of receptors, FcaRIIA, FcrRIIB, and FcrRIIC, which have different gene sequences, and all chromosomes are located on 1Q23. It has been known.
- the above-mentioned FcRIIB is an amino acid sequence that transmits an inhibitory signal to an intracellular region without associating with an A chain (ITM: Immunoreceptor Tyrosine-based Inhibition Motif) (Immunol. Rev. 125, 49-76, 1992, Science 256, 1808-1812, 1992).
- ITM Immunoreceptor Tyrosine-based Inhibition Motif
- the present inventors have already produced FcaRIIB-deficient mice (Nature 379, 346-349, 1996), and A model mouse with arthritis induced by immunization with collagen II (J. Exp. Med. 189, 187-194, 1999) and an autoimmune disease model animal were prepared (Japanese Patent Application Laid-Open No. 08-2896999). Publication).
- An object of the present invention is to provide a model non-human animal exhibiting Guillain-Barre syndrome (Fisher syndrome). More specifically, a non-human animal with Guillain-Palay syndrome onset that can be obtained by immunizing a non-human animal deficient in FcaRIIB gene with gandarioside GQlb, Guillain-Barre syndrome using the model non-human animal
- An object of the present invention is to provide a method for screening a therapeutic drug.
- the present inventors have conducted intensive studies to solve the above problems, and as a result, using FcrRIIB gene-deficient mice, gandarioside GM1, GM2, GDIa and GQ1b were subjected to Freund We immunized with an adjuvant and attempted to produce a Guillain-Barre-1 syndrome model mouse.
- gandarioside antigens peripheral neuropathy in which FqRIIB gene-deficient mice immunized with GQlb had paralyzed tail and hind limbs was observed.
- the present invention provides a Guillain-Barre, which is obtained by immunizing a non-human animal in which the function of the FcaRIIB gene is defective on the chromosome with gandriside GQ1b, and presents Guillain-Barre syndrome.
- Syndrome onset model non-human animal (Claim 1)
- the non-human animal with Guillain-Barre syndrome onset according to claim 1 or 2, wherein the non-human animal lacking FcaRIIB gene is a rodent.
- the non-human animal model for developing Guillain-Palais syndrome according to any one of claims 1 to 3, characterized in that the animal is a mouse (claim 4), and the rodent is a mouse.
- the present invention relates to a non-human animal model for developing Guillain and Barre's syndrome according to claim 5 (claim 5).
- the present invention also provides a method for administering a test substance to a Guillain-Barre syndrome model non-human animal according to any one of claims 1 to 5, and observing the degree of Guillain-Barre syndrome in the model non-human animal.
- the method of screening for a therapeutic agent for Guillain-Barre syndrome which is characterized by the evaluation (Claim 6), and the non-human animal with Guillain-Barre syndrome onset model according to any one of Claims 1 to 5,
- a screening method for a therapeutic agent for Guillain-Barré syndrome and Z or Fisher syndrome which comprises administering a test substance and measuring and evaluating the appearance of anti-GQ1b antibody (Claim 7).
- a therapeutic agent (claim 8) obtained by the method for screening a therapeutic agent for Guillain-Barre syndrome according to item 6 or 7.
- FIG. 1 shows the paralysis of the tail and hind limbs of the non-human animal model of Guillain-Palais syndrome and / or Fisher syndrome group of the present invention (upper diagram; RIIB " / -) and the control channel. It is a photograph showing a wild type mouse (lower figure; WT).
- FIG. 2 is a view showing a paralysis symptom score of a non-human animal model of Guillain-Barre syndrome and Z or Fisher syndrome group onset of the present invention and a wild-type mouse as a control.
- FIG. 3 shows serum anti-GQ1b antibodies IgG1, IgG2a and Ig of wild-type mice as non-human animals and Guillain-Barre syndrome and Z or Fisher syndrome group onset model of the present invention and control.
- FIG. 3 shows the antibody titer of G2b. BEST MODE FOR CARRYING OUT THE INVENTION
- the Guillain-Barre syndrome syndrome model non-human animal of the present invention is obtained by immunizing a non-human animal whose Fc7RIIB gene function is chromosomally deficient with gandarioside GQ1b, There is no particular limitation as long as it is a non-human animal that exhibits
- Guillain-Barré syndrome is a non-hereditary disease that is caused one to two weeks after the appearance of cold-like symptoms and rapidly progresses to flaccid motor paralysis (muscle weakness in the limbs). It is a disorder characterized by deep tendon loss, dysphagia, dysarthria, dysarthria, deep sensory disorders, and autonomic nervous symptoms (arrhythmia, fluctuations in blood pressure) and similar disorders.
- the FcrRIIB gene-deficient non-human animal of the present invention may be any model animal in which the FcRIIB gene function is deficient on the chromosome, but may be any rodent such as a mouse or rat.
- a mouse in which the function of the FcrRIIB gene is deficient on the chromosome can be preferably mentioned.
- a mouse in which the function of the FcrRIIB gene is deficient on the chromosome can be mentioned in the above-mentioned literature ( Nature 379, 346-349, 1996).
- the FcaRIIB gene is screened, and the screened FcaRIIB gene is used using a virus vector or the like. Subcloned and identified by DNA sequencing. By replacing the fragment containing the S 2 Ekison and E Ekison of this clone pMC l neo gene cassette or the like, to prepare a data one target vector.
- This linearized vector is introduced into ES cells by electroporation (electroporation) or the like, and homologous recombination is performed. Among the homologous recombinants, resistance to G418 etc. is obtained.
- the indicated ES cells are selected, and a clone of the cell is injected into the mouse blastocyst by a microphone, and the blastocyst is returned to the foster parent mouse to prepare a chimeric mouse.
- a heterozygous mouse can be obtained by intercrossing this chimeric mouse with a wild-type mouse, and an FcRIIB knockout mouse can be obtained by crossing this heterozygous mouse in and out. be able to.
- the method for producing a Guillain-Barre syndrome-onset model non-human animal includes obtaining a Guillain-Barre syndrome-onset model non-human animal. Any method can be used as long as it can be performed, and is not particularly limited.
- a preferred example is a method of immunizing the above-mentioned non-human animal deficient in Fc ⁇ RIIB gene with gandarioside GQ1b as an antigen. be able to.
- the method of immunization is not particularly limited, but is a method of immunizing with GQ1b antigen together with complete Freund's adjuvant at the time of first immunization, and immunizing with incomplete Freund's adjuvant every three weeks thereafter. Can be suitably exemplified.
- the gandarioside GQ1b used in the present invention is a glycosphingolipid produced from lactosylceramide (C er) in the b pathway synthesis system, and has four sialic acids (S ia); 3 1 ⁇ 3 (3-2 a S ia 3 2a S ia) G al NA c i3 1 ⁇ 4 G al j3 1 ⁇ 4 (3-2 cu S ia 3 ⁇ 2 a S ia) G 1 c; 8 Glycosphingolipid having a structure of 1 ⁇ 1'Cer.
- the characteristics of the GQlb are characterized by the binding form of 3-2 Sia, which is a unique sugar chain.
- specific antibodies have been obtained for each ganglioside. Since the antibodies recognizing each gandarioside recognize the difference in the binding form of the above-mentioned sugar chain 3-2 Sia, the anti-GQlb (monoclonal) antibody also binds the four 3-2 Sia. It is thought that the form was recognized specifically.
- a screen capable of confirming the pharmacological effect of the therapeutic agent and selecting by using the non-human animal model of Guillain-Palais syndrome development of the present invention.
- the method is not particularly limited, as long as it is a method for administering the test substance to a Guillain-Barré syndrome-onset model non-human animal of the present invention orally or parenterally, and the disease state is scored to obtain a time course.
- the degree of symptom degree of reduction
- the method include administering a test substance, and measuring and evaluating the degree of appearance of the anti-GQ1b antibody appearing in the blood of the model non-human animal.
- ELISA analysis using a secondary antibody can be specifically exemplified.
- the therapeutic agent for Guillain-Barre syndrome syndrome obtained by the above-mentioned screening method of the present invention can be used for treatment of a patient who has developed Guillain-Barre syndrome (Fisher syndrome).
- the therapeutic agent for Guillain-Barre syndrome according to the present invention can be administered orally or parenterally.
- Oral preparations can be solid preparations such as powders, granules, capsules and tablets or liquid preparations such as syrups and elixirs.
- parenteral preparations can be prepared as injections, transdermal preparations, suppositories and the like. These preparations can be manufactured according to a conventional method by adding a pharmacologically and pharmaceutically acceptable auxiliary to the active ingredient.
- the dose can be appropriately determined according to the type of the target disease, the age, sex, weight, symptoms, and administration form of the patient.
- the present invention will be described more specifically with reference to examples, but the technical scope of the present invention is not limited to these examples.
- Reference example (FRIRIIB-deficient mouse production)
- a genomic DNA clone of the FcaRIIB gene was isolated by screening the genomic DNA library of the 129 / Sv / J (H-2b) mouse.
- Target vector a fragment of 2. 6 5 K b comprising two independent Ekison of S 2 ⁇ beauty EC ⁇ of this clone pMC in 1 neo gene cassette (Toyobo Co., Ltd.), cowpea to replacing Produced.
- This linearized vector was introduced into ES cells (J1) by electroporation, and homologous recombination was performed.
- ES clones Isolate ES clones from ES cells that have undergone homologous recombination as described above, screen neomycin-resistant ES clones against G418 and GANC (gancyclovir), and identify homologous recombinants by Southern blotting did.
- the genomic DNA was isolated from the identified homologous recombinant and digested with Hindill to confirm that it contained a targeted allele containing the pMCl neogene cassette.
- Such confirmed ES clones are microinjected into blastocysts to produce chimeric mice, and the resulting mice are heterozygous by intercrossing with wild-type C57B LZ6 (H-2b) mice.
- mice In order to obtain zygotic mice and to obtain homozygous mice, the heterozygous mice were crossed one after another to obtain a mouse in which the function of the FCTR IIB gene was deficient on the chromosome and its wild type. Type mice were prepared.
- Example 1 Immunization of FcaRIIB gene-deficient mice
- GM1, GM2, GDla, GDlb and GQ1b (all manufactured by ALEXIS) were used as gandariosides.
- CFA complete Freund's adjuvant
- Two types of emulsions were prepared by mixing 1 g 1 of a gandarioside solution containing 1 mg Zm 1 of each gandarioside and 3 mg Zml of incomplete Freund's adjuvant (IFA) consisting of liquid paraffin and a surfactant in a connected syringe.
- IFA incomplete Freund's adjuvant
- GQ1b-immunized wild-type mice and FcrRIIB gene-deficient mice were scored according to their symptoms. 0 points: no symptoms, 1 point: paralysis of the tail, 2 points: tail and bilateral hind limbs Paralysis, 3 points: tail and limb paralysis, 4 points: death.
- the results are shown in FIG. In FIG. 2, the scores of wild-type mice are represented by black squares (garden), and the scores of FcrR R gene-deficient mice are represented by white squares (mouth).
- mice immunized with FQRIIB gene-deficient mice immunized with GQ1b developed Guillain-Barre-1 syndrome (Fitzshire syndrome) (FIG. 2).
- Example 3 Serum antibody titer against GQ 1b
- the FcaRIIB knockout mouse ( ⁇ —K ⁇ ) has a higher antibody titer (GgI, IgG2a, Ig) against GQlb than the wild-type mouse (WiId). G2b) elevation was observed, which is consistent with the findings of Guillain-Barré syndrome (Fisher's syndrome).
- the non-human animal model of Guillain-Paraie syndrome and / or Fisher's syndrome of the present invention exhibits paralysis in the tail and hind limbs and has a high antibody titer against gandarioside. It can be regarded as developing symptoms that match the type of Fisher's syndrome, and can be used for the development of treatment methods and therapeutics for these symptoms.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03770050A EP1563729A4 (en) | 2002-10-29 | 2003-10-29 | NON-MUSHROOM MODEL animal with GUILLAIN-BARRE SYNDROME AND / OR FISHER SYNDROME |
US10/533,700 US7309810B2 (en) | 2002-10-29 | 2003-10-29 | Nonhuman model animal suffering from Guillain-Barré syndrome and/or fisher syndrome |
Applications Claiming Priority (2)
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JP2002315091A JP2004147535A (ja) | 2002-10-29 | 2002-10-29 | ギラン・バレー症候群及び/又はフィッシャー症候群発症モデル非ヒト動物 |
JP2002-315091 | 2002-10-29 |
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WO2004039149A1 true WO2004039149A1 (ja) | 2004-05-13 |
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PCT/JP2003/013958 WO2004039149A1 (ja) | 2002-10-29 | 2003-10-29 | ギラン・バレー症候群及び/又はフィッシャー症候群発症モデル非ヒト動物 |
Country Status (4)
Country | Link |
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US (1) | US7309810B2 (ja) |
EP (1) | EP1563729A4 (ja) |
JP (1) | JP2004147535A (ja) |
WO (1) | WO2004039149A1 (ja) |
Families Citing this family (7)
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GB0129260D0 (en) * | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
TWI489994B (zh) | 2008-03-17 | 2015-07-01 | Baxter Healthcare Sa | 供免疫球蛋白及玻尿酸酶之皮下投藥之用的組合及方法 |
MX2012003282A (es) | 2009-09-17 | 2012-04-30 | Baxter Healthcare Sa | Co-formulacion estable de hialuronidasa e inmunoglobulina, y metodos de su uso. |
ES2671188T3 (es) | 2009-12-21 | 2018-06-05 | Regeneron Pharmaceuticals, Inc. | Ratones Fc gamma R humanizados |
US8883496B2 (en) | 2009-12-21 | 2014-11-11 | Regeneron Phamaceuticals, Inc. | Humanized FcgR mice |
JP6652931B2 (ja) | 2014-04-08 | 2020-02-26 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | ヒト化Fcγ受容体を有する非ヒト動物 |
CA3093850A1 (en) | 2018-03-26 | 2019-10-03 | Regeneron Pharmaceuticals, Inc. | Humanized rodents for testing therapeutic agents |
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JP3570674B2 (ja) * | 1999-12-28 | 2004-09-29 | 独立行政法人 科学技術振興機構 | リウマチ関節炎好発モデル動物 |
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- 2002-10-29 JP JP2002315091A patent/JP2004147535A/ja active Pending
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- 2003-10-29 US US10/533,700 patent/US7309810B2/en not_active Expired - Fee Related
- 2003-10-29 EP EP03770050A patent/EP1563729A4/en not_active Withdrawn
- 2003-10-29 WO PCT/JP2003/013958 patent/WO2004039149A1/ja active Application Filing
Non-Patent Citations (5)
Title |
---|
ODAKA M. ET AL.: "N-glycoylneuraminic acid-containing GM1 is a new molecule for serum antiubody in Guillain-Barre syndrome", ANN. NEUROL., vol. 43, no. 6, 1998, pages 829 - 834, XP002979145 * |
See also references of EP1563729A4 * |
SUSUKI KEIICHIRO ET AL.: "Jikusakugata Guillain-Barre shokogun model dobutsu no joritsu: 2nd report", MEN'EKISEI SHINKEI SHIKKAN NI KANSURU CHOSA KENKYUHAN HEISEI 12 NENDO KENKYU HOKOKUSHO, 2001, pages 111 - 112, XP002979146 * |
TAKAI T. ET AL.: "Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice", NATURE, vol. 379, no. 6563, 1996, pages 346 - 349, XP002933124 * |
YUASA T. ET AL.: "Deletion of fcgamma receptor IIB renders H-2(b) mice susceptible to collagen-induced arthritis", J. EXP. MED., vol. 189, no. 1, 1999, pages 187 - 194, XP002932700 * |
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Publication number | Publication date |
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US20070016966A1 (en) | 2007-01-18 |
JP2004147535A (ja) | 2004-05-27 |
EP1563729A4 (en) | 2008-05-14 |
US7309810B2 (en) | 2007-12-18 |
EP1563729A1 (en) | 2005-08-17 |
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