皮膚免疫の多様性形成における樹状細胞の役割の解明

• Project/Area Number: 12J04619
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: 皮膚科学
• Research Institution: Kyoto University
• Principal Investigator: 江川 形平 京都大学, 医学研究科, 特別研究員(PD)
• Project Period (FY): 2012 – 2014
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,960,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2012: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: 樹状細胞 / T細胞 / 抗原提示 / イメージング / 皮膚免疫

Outline of Annual Research Achievements

■炎症時に皮内に形成されるリンパ節様構造(induced Skin-associated lymphoid tissue)の同定
接触皮膚炎は、免疫学的には感作相と惹起相の二相に分類される。惹起相における「皮内でのT細胞の活性化」は、皮膚獲得免疫応答における重要なステップであるが、そのメカニズムについては未解明の点が多い。そこで惹起相における真皮樹状細胞およびT細胞の動態を、ライブイメージング技術を用いて解析した。すると惹起前にはランダムに分布し盛んに動き回っていた真皮樹状細胞が、惹起後徐々に集まってクラスターを形成することを発見した。クラスターは主として真皮血管周囲に形成され、また同部位にはT細胞も集積した。すなわち、皮膚の中に「抗原提示の場」が誘導形成されたのである。次にどの様なメカニズムでクラスターが誘導されるのかを検討した。さまざまな遺伝子改変マウス、中和抗体を用いて好中球、好塩基球、肥満細胞、T細胞、B細胞それぞれを欠くマウスを用いてクラスター形成の程度を検討したが、障害されなかった。しかし、皮膚の組織マクロファージを除去すると著明にクラスター形成が障害された。真皮樹状細胞クラスターは感作相でも観察されたことから、マクロファージが何らかの危険信号(danger signal)を介して活性化されていると考えられた。そこで、表皮角化細胞が産生する代表的なdanger signalであるIL-1αシグナルを中和抗体で阻害したところ、クラスター形成が著明に抑制されることを発見した。またIL-1α刺激によりM2マクロファージに作用し、CXCL2発現を強く誘導すること、さらには同サイトカインの阻害でクラスター形成、ひいては接触皮膚炎応答も障害することを明らかにした。

Current Status of Research Progress

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

Reason

皮内における樹状細胞、T細胞のクラスター形成の可視化に成功し、樹状細胞、マクロファージ、T細胞による皮内での抗原提示メカニズムを明らかにした。研究は当初の予定通りに進んだ。

Strategy for Future Research Activity

本研究の成果は、専門誌に投稿し受理された。今後は、皮内での抗原提示がT細胞にどのような影響を与えるのかを検討することを予定している。

Research Products

• [Journal Article] Dermal Vγ4(+) γδ T Cells Possess a Migratory Potency to the Draining Lymph Nodes and Modulate CD8(+) T-Cell Activity through TNF-α Production. (2015)
  • Author(s): Nakamizo S, Egawa G, Tomura M, Sakai S, Tsuchiya S, Kitoh A, Honda T, Otsuka A, Nakajima S, Dainichi T, Tanizaki H, Mitsuyama M, Sugimoto Y, Kawai K, Yoshikai Y, Miyachi Y, Kabashima K.
  • Journal Title: Journal of Investigative Dermatology Volume: 135 Issue: 4 Pages: 1007-1015
  • DOI: 10.1038/jid.2014.516
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Commensal bacteria and cutaneous immunity. (2015)
  • Author(s): Nakamizo S, Egawa G, Honda T, Nakajima S, Belkaid Y, Kabashima K.
  • Journal Title: Seminars in Immunopathology Volume: 37 Issue: 1 Pages: 73-80
  • DOI: 10.1007/s00281-014-0452-6
  • Peer Reviewed
• [Journal Article] A line of human keratin 5-Cre transgenic mice harbor a risk of ubiquitous Cre-recombination (2014)
  • Author(s): Nakagawa Y, Egawa G, Miyachi Y, Kabashima K.
  • Journal Title: Journal of Dermatological Science Volume: 76 Issue: 3 Pages: 264-7
  • DOI: 10.1016/j.jdermsci.2014.10.006
  • Peer Reviewed
• [Journal Article] Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin. (2014)
  • Author(s): Natsuaki Y, Egawa G, Nakamizo S, Ono S, Hanakawa S, Okada T, Kusuba N, Otsuka A, Kitoh A, Honda T, Nakajima S, Tsuchiya S, Sugimoto Y, Ishii KJ, Tsutsui H, Yagita H, Iwakura Y, Kubo M, Ng Lg, Hashimoto T, Fuentes J, Guttman-Yassky E, Miyachi Y, Kabashima K
  • Journal Title: Nature Immunology Volume: 15 Issue: 11 Pages: 1064-9
  • DOI: 10.1038/ni.2992
  • Peer Reviewed
• [Journal Article] Epicutaneous detection of transepidermally eliminated collagen by multiphoton microscopy : a possible non-invasive diagnosis method for acquired reactive perforating dermatosis. (2014)
  • Author(s): Murata T, Honda T, Egawa G, Miyachi Y, Kabashima K.
  • Journal Title: Journal of dermatological science Volume: 76 Issue: 2 Pages: 158-60
  • DOI: 10.1016/j.jdermsci.2014.08.004
  • Peer Reviewed
• [Journal Article] Intravital multiphoton imaging of cutaneous immune responses (2014)
  • Author(s): Kabashima K, Egawa G.
  • Journal Title: Journal of Investigative Dermatology Volume: 134 Issue: 11 Pages: 2680-4
  • DOI: 10.1038/jid.2014.225
  • Peer Reviewed
• [Journal Article] Natural killer T cells are essential for the development of contact hy persensitivity in BALB/c mice. (2014)
  • Author(s): Shimizuhira C, Otsuka A, Honda T, Kitoh A, Egawa G, Nakajima S, Nakashima C, Watarai H, Miyachi Y, Kabashima K.
  • Journal Title: Journal of Investigative Dermatology Volume: 134 Issue: 11 Pages: 2709-18
  • DOI: 10.1038/jid.2014.200
  • Peer Reviewed
• [Journal Article] Basophils regulate the recruitment of eosinophils in a murine model of irritant contact dermatitis. a K. (2014)
  • Author(s): Nakashima C, Otsuka A, Kitoh A, Honda T, Egawa G, Nakajima S, Nakamizo S, Arita M, Kubo M, Miyachi Y, Kabashim
  • Journal Title: Journal of Clinical Immunology Volume: 134 Issue: 1 Pages: 100-7
  • DOI: 10.1016/j.jaci.2014.02.026
  • Peer Reviewed
• [Journal Article] IL-17A as an Inducer for Th2 Immune Responses in Murine Atopic Dermatitis Models. (2014)
  • Author(s): Nakajima S, Kitoh A, Egawa G, Natsuaki Y, Nakamizo S, Moniaga CS, Otsuka A, Honda T, Hanakawa S, Amano W, Iwakura Y, Nakae S, Kubo M, Miyachi Y, Kabashima K
  • Journal Title: Journal of Investigative Dermatology Volume: 134 Issue: 8 Pages: 2122-30
  • DOI: 10.1038/jid.2014.51
  • Peer Reviewed
• [Journal Article] Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression. (2014)
  • Author(s): Otsuka A, Doi H, Egawa G, Maekawa A. Fujita T, Nakamizo S, et al.
  • Journal Title: J Allergy Clin Immunol. Volume: 133(1) Issue: 1 Pages: 139-46
  • DOI: 10.1016/j.jaci.2013.07.027
  • Peer Reviewed
• [Journal Article] Digital Vasculitis with Eosinophilia Possibly Associated with Etanerce pt Therapy. (2014)
  • Author(s): Nakahigashi K, Egawa G, Miy achi Y, Kabashima K.
  • Journal Title: Acta Dermto Venereologica. Volume: 94(2) Issue: 2 Pages: 239-40
  • DOI: 10.2340/00015555-1662
  • Peer Reviewed
• [Journal Article] Intravital analysis of vascular permeability in mice using two-photon microscopy. (2013)
  • Author(s): Egawa G, Nakamizo S., et al.
  • Journal Title: Sci Rep. Volume: 3 Issue: 1 Pages: 1932-1932
  • DOI: 10.1038/srep01932
  • Peer Reviewed
• [Journal Article] Calcipotriol modulates IL-22 receptor expression and keratinocyte prol iferation in IL-22-induced epidermal hyperplasia. (2013)
  • Author(s): Moniaga CS, Egawa G, Miyac hi Y, Kabashima K.
  • Journal Title: Journal of dermatological science Volume: 76(1) Pages: 76-77
  • Peer Reviewed
• [Journal Article] Basophils are required for the induction of Th2 immunity to haptens and peptide antigens. (2013)
  • Author(s): Otsuka A, Nakajima S, Kubo M, Egawa G, Honda T, Kitoh A, Nomura T, Hanakawa S, Sagita Moniaga C, Kim B, Matsuoka S, Watanabe T, Miyachi Y , Kabashima K.
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1739-1739
  • DOI: 10.1038/ncomms2740
  • Peer Reviewed
• [Journal Article] Identification of perivascular adipose tissue in the mouse skin using t wo-photon microscopy. (2013)
  • Author(s): Egawa G, Miyachi Y, Kabashima K.
  • Journal Title: Journal of dermatological science Volume: 70(2) Pages: 139-40
  • Peer Reviewed
• [Journal Article] Hydrolyzed wheat protein-containing facial soap-induced wheat-dependent exercise-induced anaphylaxis in a patient without filaggrin mutations. (2013)
  • Author(s): Iga N, Tanizaki H, Endo Y, Egawa G, Fujisawa A, Tanioka M,
  • Journal Title: Journal of Dermatology Volume: 40 Issue: 6 Pages: 494-495
  • DOI: 10.1111/1346-8138.12124
  • Peer Reviewed
• [Journal Article] Three-dimensional imaging of epidermal keratinocytes and dermal vasculatures using two-photon microscopy. (2013)
  • Author(s): Egawa G, Natsuaki Y, Miyachi Y, Kabashima K.
  • Journal Title: Journal of Dermatological Science Volume: 70 Issue: 2 Pages: 143-145
  • DOI: 10.1016/j.jdermsci.2013.01.005
  • Peer Reviewed
• [Journal Article] Skin tape stripping and cheek swab method for a detect ion of filaggrin. (2013)
  • Author(s): Egawa G, DOI H, Miyachi Y, Kabashima K.
  • Journal Title: Journal of Dermatological Science Volume: 69 Pages: 263-265
  • Peer Reviewed
• [Journal Article] PCR-RFLP analysis for S2889X in filaggrin harbors the risk of a typing error. (2013)
  • Author(s): Egawa G, DOI H, Miyacni Y, Kabashima K.
  • Journal Title: Journal of Dermatological Science Volume: 69 Issue: 3 Pages: 262-263
  • DOI: 10.1016/j.jdermsci.2012.11.007
  • Peer Reviewed
• [Journal Article] Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice. (2013)
  • Author(s): Moniaga CS, Jeong SK, Egawa G, Nakajima S, 他6名
  • Journal Title: American Journal of Pathology Volume: 182 Issue: 3 Pages: 841-851
  • DOI: 10.1016/j.ajpath.2012.11.039
  • Peer Reviewed
• [Journal Article] Update of immune events in the murine contact hypersensitivi ty model : toward the understanding of allergic contact dermatitis. (2012)
  • Author(s): Honda T, Egawa G, Grabbe S, Kabashima K.
  • Journal Title: Journal of Investigative Dermatology Volume: 133 Issue: 2 Pages: 303-315
  • DOI: 10.1038/jid.2012.284
  • Peer Reviewed
• [Journal Article] Oral allergy syndrome complicated with multiple food sensitization detected by specific IgES. (2012)
  • Author(s): Shibuya R, Tanizalu H, Egawa G, Doi H, Fuiisawa A, Tanioka M,
  • Journal Title: Europian Journal of Dermatology Volume: 22 Issue: 4 Pages: 572-573
  • DOI: 10.1684/ejd.2012.1766
  • Peer Reviewed
• [Journal Article] Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin (2012)
  • Author(s): 中島沙恵子、椛島健治, 他
  • Journal Title: The journal of allergy and clinical immunology Volume: 129 Issue: 4 Pages: 1048-1055
  • DOI: 10.1016/j.jaci.2012.01.063
  • Peer Reviewed
• [Presentation] lnvolucrin-mOVAマウスを用いた皮膚自己免疫モデルの解析 (2014)
  • Author(s): 江川形平
  • Organizer: 日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル・東京
  • Year and Date: 2014-09-25
  • Invited
• [Presentation] Two distinct subsets of skin-infiltrating memory T cells, TRM and TEM, define cutaneous immune responses against systemically-administered soluble antigens (2014)
  • Author(s): 江川形平
  • Organizer: アメリカ研究皮膚科学会
  • Place of Presentation: アルバカーキ・アメリカ
  • Year and Date: 2014-05-09
• [Presentation] Two distinct subsets of skin-infiltrating memory T cells, T_<RM> and T_<EM>, define cutaneous immune responses against systemically-administered soluble antigens (2014)
  • Author(s): 江川形平
  • Organizer: アメリカ免疫学会
  • Place of Presentation: ピッツバーグ・アメリカ
  • Year and Date: 2014-05-03
• [Presentation] Revealing the motility of tissue-resident memory T cells (T_<RM>) by deveh ping a novel murine model of fixed drug eruption (2013)
  • Author(s): 江川形平
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張メッセ・千葉県
  • Year and Date: 2013-12-12
• [Presentation] 接触皮膚炎発症機序の字空間的解析 (2013)
  • Author(s): 江川形平
  • Organizer: 日本アレルギー・接触皮膚炎学会
  • Place of Presentation: ホテル日航金沢・金沢市
  • Year and Date: 2013-11-29
  • Invited
• [Presentation] Decreased adhesion of keratinocytes via E-cadherin downmodulation is a platform for leukocytes mobility in the epidermis (2013)
  • Author(s): 江川形平
  • Organizer: 国際研究皮膚科学会
  • Place of Presentation: Edinburgh、英国
  • Year and Date: 2013-05-10
• [Presentation] Intercellular gap of keratinoeytes is a migratory pathway for epidermal Langerhans cells (2012)
  • Author(s): 江川形平
  • Organizer: 日本研究皮膚科学会
  • Place of Presentation: ロワジールホテル、沖縄県
  • Year and Date: 2012-12-08
• [Presentation] ランゲルハンス細胞は表皮角化細胞間隙を移動する (2012)
  • Author(s): 江川形平
  • Organizer: 日本免疫学会
  • Place of Presentation: 神戸国際会議場、兵庫県
  • Year and Date: 2012-12-05
• [Presentation] Intercellular gap of keratinocytes is a migratory pathway for epidermal Langerhans cells (2012)
  • Author(s): 江川形平
  • Organizer: 国際楔状細胞研究会
  • Place of Presentation: 大邸市、韓国
  • Year and Date: 2012-10-07
• [Presentation] 当院における生物学的製剤使用患者50症例のまとめ (2012)
  • Author(s): 江川形平
  • Organizer: 日本乾癬学会
  • Place of Presentation: 朱鷺メッセ、新潟県
  • Year and Date: 2012-09-07