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ATOPIC DERMATITIS MODEL ANIMAL AND USE THEREOF meetings

Foreign code F150008351
File No. S2013-0593-C0
Posted date Jun 11, 2015
Country WIPO
International application number 2014JP061931
International publication number WO 2014178392
Date of international filing Apr 30, 2014
Date of international publication Nov 6, 2014
Priority data
  • P2013-096637 (May 1, 2013) JP
Title ATOPIC DERMATITIS MODEL ANIMAL AND USE THEREOF meetings
Abstract Provided are a transgenic nonhuman mammal that holds a DNA encoding IL-33 in a state of being expressible specifically in the skin, etc., when fed under specific pathogen free (SPF) conditions, said transgenic nonhuman mammal having, compared with a non-transgenic nonhuman mammal corresponding thereto, one or more characteristics selected from the group consisting of: (1) spontaneously developing dermatitis; (2) showing an increase in inflammatory cell count; (3) showing an increase in total IgE concentration, histamine concentration, cytokine concentration and/or chemokine concentration; and (4) showing an increase in scratching behavior time.
Outline of related art and contending technology BACKGROUND ART
Atopic dermatitis is, pruritic, chronic inflammatory skin disorder and repetitive, have a genetic background, with a high level in the blood serum IgE and. In addition, eosinophils and mast cells at the lesion site is collected, blood eosinophils also increases. The onset mechanism of atopic dermatitis is still not completely elucidated, cell activation T, on mast cells or basophils bound immunoglobulin Fc ε R (hereinafter, referred to as Ig) cross linking of the molecules E induced by mast cells and basophils consequence of the activation of, chemical mediators and cytokines associated with the generation of Th2 occurs is considered important. The cytokines, interleukins (hereinafter, referred to as IL) -4, IL-13, and IL-5, chemical mediators and histamine, serotonin and the like. In this case, in particular the activation of mast cells and basophils is antigen-specific IgE is an important role, antigen specificity is not apparent in the case of natural type atopic dermatitis, is not limited to, an external stimulus and infections, such as IL-18 is implicated, details remain unknown.
Genetically engineered atopic dermatitis model mouse as the system 7 'IL-4 Tg, CASP1 Tg, IL-18 Tg, IL-31 Tg, Re1B-KO, (non-patent document 1) CatE-KO, MAIL-KO(non-patent document 2) ' is reported.
However, produced by genetically engineered mouse model of atopic dermatitis is atopic dermatitis actually does not always reflect the feature. For example, produced by genetic engineering atopic dermatitis model was reported as some of the model, high expression of the gene is localized in the patient's skin to atopic dermatitis enhanced expression of a gene not normally found in a model (CASP1 Tg, IL-18 Tg, IL-4 Tg), dermatitis or tissue eosinophils in neutrophil but also, with no change to the value of the IgE (IL-31 Tg), with characteristics such as human atopic dermatitis model to appropriately reflect the disease is not necessarily considered. In addition to the mice do not exhibit symptoms Pruritus RelB-KO, MAIL - KO mice (IkB ζ) perinatal mortality rate is very high, the high stringency condition is inflammation such as in terms of atopic dermatitis model is incomplete. Therefore, these model mice of atopic dermatitis in the case of using the evaluation, there is a concern that does not reflect the actual condition.
However, in recent years include atopic dermatitis research progresses, new knowledge has been created. Recently, atopic dermatitis skin of the patient's skin keratinocytes in the nuclei of the cells, an increased expression level of IL-33 has been reported (non-patent document 3). IL-33 IL-1β IL-18 and is highly homologous with the amino acid sequence identified as belonging to the family cytokine IL-1 is, ST2 to its receptor. ST2 Th2 Of the cells involved in the cell or allergy (basophils, mast cells, eosinophils, natural type 2 lymphocytes) can be expressed on, Th2 is involved in a disease of allergy IL-33 is suggested. However, mouse recombinant IL-33 directly administering locally within the dermis of the skin and, associated with increased dermal collagen fibers scleroderma-like reaction occurs, with or without the change of the epidermis (non-patent document 4) and reported to, epidermal thickening with psoriasis-like skin (non-patent document 5) occurs and a report that the, the influence on the skin of the IL-33 is not clear. Under the present circumstances such, until now IL-33 highly expressed in the skin in a transgenic animal that is not present, their phenotype was also remain unclear.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 IL-33をコードするDNAを皮膚において特異的に発現可能な状態で保持するトランスジェニック非ヒト哺乳動物であって、SPF(specific pathogen free)の飼育条件下で、対応する非トランスジェニック非ヒト哺乳動物と比較して
(1)皮膚炎を自然発症する、
(2)炎症細胞数が増加している、
(3)総IgE濃度、ヒスタミン濃度、サイトカイン濃度および/またはケモカイン濃度が増加している、および
(4)掻破行動時間が増加している
からなる群から選択される特徴を1つ以上有する、非ヒト哺乳動物。

[請求項2]
 IL-33をコードするDNAがケラチンプロモーターの制御下にある、請求項1に記載の非ヒト哺乳動物。

[請求項3]
 ケラチンプロモーターがヒトケラチン14プロモーターである、請求項2記載の非ヒト哺乳動物。

[請求項4]
 IL-33が配列番号:2で表されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する請求項1~3のいずれか1項に記載の非ヒト哺乳動物。

[請求項5]
 炎症細胞が好酸球、肥満細胞および2型自然リンパ球からなる群から選択される細胞である、請求項1~4のいずれか1項に記載の非ヒト哺乳動物。

[請求項6]
 サイトカインがIL-4、IL-5またはIL-13である、請求項1~5のいずれか1項に記載の非ヒト哺乳動物。

[請求項7]
 ケモカインがCCL2、CCL4、CCL5またはCCL11である、請求項1~6のいずれか1項に記載の非ヒト哺乳動物。

[請求項8]
 掻破行動時間または皮膚炎の症状が抗ヒスタミン薬またはステロイド薬によって低減することを特徴とする、請求項1~7のいずれか1項に記載の非ヒト哺乳動物。

[請求項9]
 非ヒト哺乳動物がマウスである、請求項1~8のいずれか1項に記載の非ヒト哺乳動物。

[請求項10]
 SPF(specific pathogen free)の飼育条件下で、請求項1~9のいずれか1項に記載の非ヒト哺乳動物に試験化合物を適用し、(1)皮疹スコア、(2)炎症細胞数、(3)総IgE濃度、ヒスタミン濃度、サイトカイン濃度および/またはケモカイン濃度、および(4)掻破行動時間からなる群から選択される項目を1つ以上測定し、測定された前記項目を試験化合物非投与の場合と比べて改善させる試験物質を選択することを含む、アトピー性皮膚炎治療薬のスクリーニング方法。

[請求項11]
 SPF(specific pathogen free)の飼育条件下で、請求項1~9のいずれか1項に記載の非ヒト哺乳動物にアトピー性皮膚炎の予防・治療薬を適用し、(1)皮疹スコア、(2)炎症細胞数、(3)総IgE濃度、ヒスタミン濃度、サイトカイン濃度および/またはケモカイン濃度、および(4)掻破行動時間からなる群から選択される項目を1つ以上測定し、測定された前記項目をアトピー性皮膚炎の予防・治療薬非投与の場合と比べる、アトピー性皮膚炎の予防・治療薬の効果の評価方法。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • HYOGO COLLEGE OF MEDICINE
  • MIE UNIVERSITY
  • Inventor
  • YAMANISHI, Kiyofumi
  • MIZUTANI, Hitoshi
  • IMAI, Yasutomo
  • YOSHIMOTO, Tomohiro
  • NAKANISHI, Kenji
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN TD TG

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