ヒト白斑モデルTh17型マウスを用いた白斑発症機構の解明

2015 Fiscal Year Research-status Report

• Project/Area Number: 15K15418
• Research Institution: Osaka University
• Principal Investigator: 片山 一朗 大阪大学, 医学(系)研究科(研究院), 教授 (80191980)
• Co-Investigator(Kenkyū-buntansha): 荒瀬 規子 大阪大学, 医学(系)研究科(研究院), 特任研究員 (30360481) ; 楊 伶俐 大阪大学, 医学(系)研究科(研究院), 特任研究員 (40711784) ; 越智 沙織 大阪大学, 医学(系)研究科(研究院), 助教 (00597495)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 白斑 / Th17 / モデルマウス / メラノサイト / MHC

Outline of Annual Research Achievements

自己免疫性汎発型白斑発症にCD8+T細胞が重要であることは、過去多く報告がある。しかし、実際の白斑皮膚において真皮上層・表皮内にCD8+T細胞が浸潤しているが、メラノサイトと近接し障害する像や、基底膜障害に伴うメラニンの滴落・貪食像はほとんど認めない。そこで我々は炎症性皮膚疾患に関与する多くの炎症細胞の局所浸潤を調べたところ、尋常性乾癬やアトピー性皮膚炎の病態形成に役割を担うTh17細胞の浸潤を見いだした。さらに、IL-1β，IL-6，TNF-α，IL-17AなどのTh17細胞に関連したサイトカインで培養メラノサイトを処理したところ、メラニン生合成に関与する転写因子や酵素関連因子の発現が有意に低下し、同時にメラニン合成も抑制された。Th17細胞関連サイトカインはT細胞に表皮角化細胞や真皮線維芽細胞が協調的に作用することで促進される事が分かり、白斑局所に於いて細胞間同士でサイトカインを介する微小環境が形成される可能性が示唆された。そこで我々は、Th17型トランスジェニックマウスに種々の物理・化学的刺激、微生物由来物質等を加える系で白斑誘導を試みようと考えた。さらに、マウスMHCにメラノサイト抗原を提示させる系を確立しメラノサイト特異免疫を誘導させ白斑発症を試みることを考えた。現在、TH17トランスジェニックマウスを作成中である。さらに種々のマウスメラノサイト関連抗原のクローニングを進めている。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

Th17トランスジェニックマウスの凍結胚の移行手続きに時間を要した。
マウスメラノサイト抗原の遺伝子クローニング、MHCの遺伝子クローニングはおおむね順調に進んでいる。

Strategy for Future Research Activity

トランスジェニックマウス作成と、メラノサイト関連蛋白のMHC提示の予備実験を進め、マウスの白斑発症を試みる。

Causes of Carryover

トランスジェニックマウス作成まで至らず、マウスの飼育の費用等が次年度に持ち越された。

Expenditure Plan for Carryover Budget

トランスジェニックマウス作成と、メラノサイト関連蛋白のMHC提示の予備実験を進め、マウスの白斑発症を試みる。

Research Products

• [Journal Article] Increased serum CXCR2 ligand levels in livedo vasculopathy with winter ulcerations: Possible contribution of neutrophil recruitment to lesional skin. (2016)
  • Author(s): Yang L, Murota H, Shindo S, Yang F, Serada S, Fujimoto M, Naka T, Katayama I
  • Journal Title: J Dermatol Sci. Volume: 82 Pages: 57-9
  • DOI: http://dx.doi.org/10.1016/j.jdermsci.2016.01.004
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia in Japanese patients with tuberous sclerosis complex. (2016)
  • Author(s): Tanaka M, Hirata H, Wataya-Kaneda M, Yoshida M, Katayama I
  • Journal Title: Respir Investig. Volume: 54 Pages: 8-13
  • DOI: 10.1016/j.resinv.2015.06.003. Epub 2015 Oct 29.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] B-1 B cell progenitors transiently and partially express keratin 5 during differentiation in bone marrow. (2016)
  • Author(s): Hanafusa T, Kato K, Azukizawa H, Miyazaki J, Takeda J, Katayama I
  • Journal Title: J Dermatol Sci. Volume: 81 Pages: 173-81
  • DOI: 10.1016/j.jdermsci.2015.11.010. Epub 2015 Nov 30.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Unique case of postural cholinergic urticaria induced by a standing position. (2016)
  • Author(s): Hirohata A, Yamaoka T, Hayashi M, Murota H, Tani M, Katayama I.
  • Journal Title: Clin Exp Dermatol. Volume: ahead of print Pages: ahead of print
  • DOI: 10.1111/ced.12796.
  • Peer Reviewed
• [Journal Article] Evolving understanding on the aetiology of thermally provoked itch. (2016)
  • Author(s): Murota H, Katayama I.
  • Journal Title: Eur J Pain. Volume: 20 Pages: 47-50
  • DOI: 10.1002/ejp.777.
  • Peer Reviewed
• [Journal Article] Psoriatic Arthritis Complicating Systemic Sclerosis: Possible Involvement of M2 Macrophages. (2015)
  • Author(s): Yamaoka T, Inoue T, Kitaba S, Yokomi A, Azukizawa H, Terao M, Murota H, Higashiyama M, Katayama I.
  • Journal Title: Ann Dermatol. Volume: 27 Pages: 631-2
  • DOI: 10.5021/ad.2015.27.5.631.
  • Peer Reviewed
• [Journal Article] A vitamin D analog inhibits Th2 cytokine- and TGFβ -induced periostin production in fibroblasts: a potential role for vitamin D in skin sclerosis. (2015)
  • Author(s): Terao M, Yang L, Matsumura S, Yutani M, Murota H, Katayama I.
  • Journal Title: Dermatoendocrinol. Volume: 7 Pages: e1010983
  • DOI: 10.1080/19381980.2015.1010983.
  • Peer Reviewed
• [Journal Article] Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. (2015)
  • Author(s): Hirobe S, Azukizawa H, Hanafusa T, Matsuo K, Quan YS, Kamiyama F, Katayama I, Okada N, Nakagawa S.
  • Journal Title: Biomaterials. Volume: 57 Pages: 50-8
  • DOI: 10.1016/j.biomaterials.2015.04.007.
  • Peer Reviewed
• [Journal Article] Oligosaccharide modification by N-acetylglucosaminyltransferase-V in macrophages are involved in pathogenesis of bleomycin-induced scleroderma. (2015)
  • Author(s): Kato A, Yutani M, Terao M, Kimura A, Itoi S, Murota H, Miyoshi E, Katayama I.
  • Journal Title: Exp Dermatol. Volume: 24 Pages: 585-90
  • DOI: 10.1111/exd.12730.
  • Peer Reviewed
• [Journal Article] NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation. (2015)
  • Author(s): Namiki T, Yaguchi T, Nakamura K, Valencia JC, Coelho SG, Yin L, Kawaguchi M, Vieira WD, Kaneko Y, Tanemura A, Katayama I, Yokozeki H, Kawakami Y, Hearing VJ.
  • Journal Title: Cancer Res. Volume: 75 Pages: 2708-15
  • DOI: 10.1158/0008-5472.CAN-13-3209.
  • Peer Reviewed
• [Journal Article] Th2 cytokines enhance TrkA expression, upregulate proliferation, and downregulate differentiation of keratinocytes. (2015)
  • Author(s): Matsumura S, Terao M, Murota H, Katayama I.
  • Journal Title: J Dermatol Sci. Volume: 78 Pages: 215-23
  • DOI: 10.1016/j.jdermsci.2015.02.021.
  • Peer Reviewed
• [Journal Article] Factors associated with the development and remission of allergic diseases in an epidemiological survey of high school students in Japan. (2015)
  • Author(s): Tokunaga T, Ninomiya T, Osawa Y, Imoto Y, Ito Y, Takabayashi T, Narita N, Kijima A, Murota H, Katayama I, Fujieda S.
  • Journal Title: Am J Rhinol Allergy. Volume: 29 Pages: 94-9
  • DOI: 10.2500/ajra.2015.29.4135.
  • Peer Reviewed
• [Journal Article] β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. (2015)
  • Author(s): Tanimura K, Jin H, Suenaga T, Morikami S, Arase N, Kishida K, Hirayasu K, Kohyama M, Ebina Y, Yasuda S, Horita T, Takasugi K, Ohmura K, Yamamoto K, Katayama I, Sasazuki T, Lanier LL, Atsumi T, Yamada H, Arase H.
  • Journal Title: Blood. Volume: 125 Pages: 2835-44
  • DOI: 10.1182/blood-2014-08-593624.
  • Peer Reviewed
• [Journal Article] Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex. (2015)
  • Author(s): Wataya-Kaneda M, Tanaka M, Yang L, Yang F, Tsuruta D, Nakamura A, Matsumoto S, Hamasaki T, Tanemura A, Katayama I.
  • Journal Title: JAMA Dermatol. Volume: 151 Pages: 722-30
  • DOI: 10.1001/jamadermatol.2014.4298.
  • Peer Reviewed
• [Journal Article] 4-(4-hydroroxyphenyl)-2-butanol (rhododendrol) activates the autophagy-lysosome pathway in melanocytes: insights into the mechanisms of rhododendrol-induced leukoderma. (2015)
  • Author(s): Yang L, Yang F, Wataya-Kaneda M, Tanemura A, Tsuruta D, Katayama I.
  • Journal Title: J Dermatol Sci. Volume: 77 Pages: 182-5
  • DOI: 10.1016/j.jdermsci.2015.01.006.
  • Peer Reviewed
• [Journal Article] Developing core outcome set for vitiligo clinical trials: international e-Delphi consensus. (2015)
  • Author(s): Eleftheriadou V, Thomas K, van Geel N, Hamzavi I, Lim H, Suzuki T, Katayama I, Anbar T, Abdallah M, Benzekri L, Gauthier Y, Harris J, Silva de Castro CC, Pandya A, Goh BK, Lan CC, Oiso N, Al Issa A, Esmat S, Le Poole C, Lee AY, Parsad D, Taieb A, Picardo M, Ezzedine K ; Vitiligo Global Issues Consensus Group.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 28 Pages: 363-9
  • DOI: 10.1111/pcmr.12354.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] T helper 2 polarization in senile erythroderma with elevated levels of TARC and IgE. (2015)
  • Author(s): Nakano-Tahara M, Terao M, Nishioka M, Kitaba S, Murota H, Katayama I.
  • Journal Title: Dermatology. Volume: 230 Pages: 62-9
  • DOI: 10.1159/000366502.
  • Peer Reviewed
• [Journal Article] Possible association of anti-tumor necrosis factor-α antibody therapy with the development of scleroderma-like changes with lichen planus. (2015)
  • Author(s): Inoue-Nishimoto T, Hanafusa T, Igawa K, Azukizawa H, Yokomi A, Yokozeki H, Katayama I.
  • Journal Title: Eur J Dermatol. Volume: 25 Pages: 513-5
  • DOI: 10.1684/ejd.2015.2631.
  • Peer Reviewed
• [Journal Article] Suppressor of cytokine signalling-1 induces significant preclinical antitumor effect in malignant melanoma cells. (2015)
  • Author(s): Tagami-Nagata N, Serada S, Fujimoto M, Tanemura A, Nakatsuka R, Ohkawara T, Murota H, Kishimoto T, Katayama I, Naka T.
  • Journal Title: Exp Dermatol. Volume: 24 Pages: 864-71
  • DOI: 10.1111/exd.12802.
  • Peer Reviewed
• [Journal Article] Case of Hermansky-Pudlak syndrome 1 in a Japanese infant. (2015)
  • Author(s): Tanaka M, Yang L, Wataya-Kaneda M, Suzuki T, Okamura K, Hozumi Y, Yang F, Katayama I.
  • Journal Title: J Dermatol. Volume: 42 Pages: 906-7
  • DOI: 10.1111/1346-8138.12937.
  • Peer Reviewed
• [Journal Article] Efficacy of additional i.v. immunoglobulin to steroid therapy in Stevens-Johnson syndrome and toxic epidermal necrolysis. (2015)
  • Author(s): Aihara M, Kano Y, Fujita H, Kambara T, Matsukura S, Katayama I, Azukizawa H, Miyachi Y, Endo Y, Asada H, Miyagawa F, Morita E, Kaneko S, Abe R, Ochiai T, Sueki H, Watanabe H, Nagao K, Aoyama Y, Sayama K, Hashimoto K, Shiohara T; SJS/TEN Study Group.
  • Journal Title: J Dermatol. Volume: 42 Pages: 768-77
  • DOI: 10.1111/1346-8138.12925.
  • Peer Reviewed
• [Journal Article] A rare case of mucinous carcinoma of the skin with multiple organ metastases. (2015)
  • Author(s): Tanemura A, Deguchi A, Tanaka A, Kiyohara E, Kishioka A, Katayama I.
  • Journal Title: Eur J Dermatol. Volume: 25 Pages: 483-4
  • DOI: 10.1684/ejd.2015.2545.
  • Peer Reviewed
• [Journal Article] Pyoderma gangrenosum and annular erythema associated with Sjogren's syndrome controlled with minocycline. (2015)
  • Author(s): Yamanaka K, Murota H, Goto H, Yamamoto S, Katayama I, Taniguchi Y, Mizutani H.
  • Journal Title: J Dermatol. Volume: 42 Pages: 834-6
  • DOI: 10.1111/1346-8138.12897.
  • Peer Reviewed
• [Journal Article] Possible involvement of CCR4+ CD8+ T cells and elevated plasma CCL22 and CCL17 in patients with rhododenol-induced leukoderma. (2015)
  • Author(s): Nishioka M, Tanemura A, Yang L, Tanaka A, Arase N, Katayama I.
  • Journal Title: J Dermatol Sci. Volume: 77 Pages: 188-90
  • DOI: 10.1016/j.jdermsci.2015.02.014.
  • Peer Reviewed
• [Journal Article] An immune pathological and ultrastructural skin analysis for rhododenol-induced leukoderma patients. (2015)
  • Author(s): Tanemura A, Yang L, Yang F, Nagata Y, Wataya-Kaneda M, Fukai K, Tsuruta D, Ohe R, Yamakawa M, Suzuki T, Katayama I.
  • Journal Title: J Dermatol Sci. Volume: 77 Pages: 185-8
  • DOI: 10.1016/j.jdermsci.2015.01.002.
  • Peer Reviewed
• [Journal Article] Guide for medical professionals (i.e., dermatologists) for the management of Rhododenol-induced leukoderma. (2015)
  • Author(s): Nishigori C, Aoyama Y, Ito A, Suzuki K, Suzuki T, Tanemura A, Ito M, Katayama I, Oiso N, Kagohashi Y, Sugiura S, Fukai K, Funasaka Y, Yamashita T, Matsunaga K.
  • Journal Title: J Dermatol. Volume: 42 Pages: 113-28
  • DOI: 10.1111/1346-8138.12744.
  • Peer Reviewed
• [Journal Article] Case of Behcet's disease complicated by oculomotor nerve palsy associated with internal carotid artery-posterior communicating artery aneurysm. (2015)
  • Author(s): Yamaoka T, Murota H, Katayama I.
  • Journal Title: J Dermatol. Volume: 42 Pages: 315-7
  • DOI: 10.1111/1346-8138.12752.
  • Peer Reviewed
• [Journal Article] Severe scoliosis associated with the WNT10A mutation. (2015)
  • Author(s): Koguchi-Yoshioka H, Wataya-Kaneda M, Nakano H, Tanemura A, Akasaka E, Sawamura D, Katayama I.
  • Journal Title: J Dermatol. Volume: 42 Pages: 322-3
  • DOI: 10.1111/1346-8138.12762.
  • Peer Reviewed
• [Journal Article] Atopic diathesis in hypohidrotic/anhidrotic ectodermal dysplasia. (2015)
  • Author(s): Koguchi-Yoshioka H, Wataya-Kaneda M, Yutani M, Murota H, Nakano H, Sawamura D, Katayama I.
  • Journal Title: Acta Derm Venereol. Volume: 95 Pages: 476-9
  • DOI: 10.2340/00015555-1978.
  • Peer Reviewed
• [Journal Article] Sweat, the driving force behind normal skin: an emerging perspective on functional biology and regulatory mechanisms. (2015)
  • Author(s): Murota H, Matsui S, Ono E, Kijima A, Kikuta J, Ishii M, Katayama I.
  • Journal Title: J Dermatol Sci. Volume: 77 Pages: 3-10
  • DOI: 10.1016/j.jdermsci.2014.08.011.
  • Peer Reviewed
• [Journal Article] Development of necrotising fasciitis in a patient treated for rheumatoid arthritis with tocilizumab. (2015)
  • Author(s): Hashimoto N, Yamaoka T, Koguchi-Yoshioka H, Tanaka A, Tanemura A, Azukizawa H, Murota H, Kang J, Nakagawa Y, Shimazu T, Katayama I.
  • Journal Title: Acta Derm Venereol. Volume: 95 Pages: 370-1
  • DOI: 10.2340/00015555-1952.
  • Peer Reviewed
• [Journal Article] Partial anhidrosis demonstrated by Q-SART in a patient with a novel mutation in the EDARADD gene. (2015)
  • Author(s): Koguchi-Yoshioka H, Wataya-Kaneda M, Yutani M, Nakano H, Sawamura D, Katayama I.
  • Journal Title: J Eur Acad Dermatol Venereol. Volume: 29 Pages: 1443-4
  • DOI: 10.1111/jdv.12493.
  • Peer Reviewed
• [Presentation] DIR is an innate immune sensor for microbially cleaved immunoglobulins. (2015)
  • Author(s): Kouyuki Hirayasu, Fumiji Saito, Tadahiro Suenaga, Kyoko Shida, Noriko Arase, Keita Oikawa, Toshifumi Yamaoka, Hiroyuki Murota, Hiroji Chibana, Ichiro Nakagawa, Tomoko Kubori, Hiroki Nagai, Yuji Nakamaru, Ichiro Katayama, Marco Colonna, Hisashi Arase.
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18 – 2015-11-20