ニッチによる免疫系自己形成の分子機構の解明

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 22021019
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 長澤 丘司 京都大学, 再生医科学研究所, 教授 (80281690)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥9,600,000 (Direct Cost: ¥9,600,000); Fiscal Year 2011: ¥4,800,000 (Direct Cost: ¥4,800,000); Fiscal Year 2010: ¥4,800,000 (Direct Cost: ¥4,800,000)
• Keywords: ケモカイン / 脊髄 / 造血幹細胞 / リンパ球 / ニッチ / 骨髄

Research Abstract

(1)自己識別を担う免疫担当細胞の産生・維持におけるCAR細胞の役割の解明。CAR細胞の細胞数を低下させたマウスでリンパ球前駆細胞と成熟リンパ球が著減していることが明らかになった。
(2)CAR細胞によるリンパ球前駆細胞、免疫担当細胞の制御機構の解明。世界的に骨髄の造血ニッチ細胞は培養できておらず、主要なニッチ細胞であるCAR細胞も、フローサイトメトリーで純化・分離すると従来の骨髄細胞の試験管内培養法では培養できない。そこで、CAR細胞を培養する試験管内培養系(CAR細胞骨髄ニッチ培養)の樹立を試み、増殖するCAR細胞の頻度を増加させたが、完全な培養系の樹立には至らなかった。
(3)CAR細胞の自己識別機構形成機能を調節する分子機構の解明。
CAR細胞で高発現する遺伝子の中からCAR細胞の機能調節に関与する可能性がある機能遺伝子の欠損マウスの作製を進めた。
(4)CXCL12の免疫系形成における作用の分子機構の解明。
生体骨髄より免疫担当細胞やその前駆細胞分画を分離し、試験管内でCXCL12とTPO、SCF、FL、IL-7の細胞増殖・生存・細胞周期の長さ・分化への作用を解析した。

Current Status of Research Progress

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

Reason

免疫系自己形成に重要であることが期待される遺伝子について、変異マウスの作製など解析が順調に進展しているため。

Strategy for Future Research Activity

現在の研究を継続し、免疫担当細胞の産生・自己識別能形成・維持におけるCAR細胞の役割とその作用の分子機構、CXCL12の免疫系形成における作用の分子機構の解明、CAR細胞の免疫系自己識別機能形成を調節する分子の同定,二次リンパ組織の自己識別機構の維持におけるCXCL12発現細胞の役割を解明することをめざす。

Research Products

• [Journal Article] Bone marrow niches for hematopoietic stem cells and immune cells (2012)
  • Author(s): Sugiyama, T., Nagasawa, T.
  • Journal Title: Inflamm.Allergy Drug Targets Volume: (in press)
  • NAID: 120004287995
  • Peer Reviewed
• [Journal Article] Control of hematopoietic stem cells by the bone marrow stromal niche : the role of reticular cells (2011)
  • Author(s): Nagasawa, T., Omatsu, Y., Sugiyama, T.
  • Journal Title: Trends Immunol. Volume: 32 Issue: 7 Pages: 315-320
  • DOI: 10.1016/j.it.2011.03.009
  • Peer Reviewed
• [Journal Article] Emergency evacuation! Hematopoietic niches induce cell exit in infection (2011)
  • Author(s): Sugiyama, T., Nagasawa, T.
  • Journal Title: Immunity Volume: 34 Issue: 4 Pages: 463-465
  • DOI: 10.1016/j.immuni.2011.04.009
  • Peer Reviewed
• [Journal Article] Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero (2011)
  • Author(s): Kubota Y, Takubo K, Hirashima M, Nagoshi N, Kishi K, Sano K, Murakami M, Ema M, Omatsu Y, Takahashi S, Nagasawa T, Shibuya M, Okano H, Suda T
  • Journal Title: J Exp Med Volume: 208 Issue: 5 Pages: 949-960
  • DOI: 10.1084/jem.20102187
  • Peer Reviewed
• [Journal Article] CXCL12-CXCR4 chemokine signaling is essential for NK cell development in adult mice. (2011)
  • Author(s): Noda, M.
  • Journal Title: Blood Volume: VOL.117 Pages: 451-458
  • Peer Reviewed
• [Journal Article] Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. (2011)
  • Author(s): Lei, Y.
  • Journal Title: J.Exp.Med. Volume: VOL.208 Pages: 383-394
  • Peer Reviewed
• [Journal Article] C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase_in myeloid differentiation antigen (Gr-1)-positive cells. (2011)
  • Author(s): Hiratsuka, S.
  • Journal Title: Proc.Nat.l Acad.Sci, U S A. Volume: VOL.108 Pages: 302-307
  • Peer Reviewed
• [Journal Article] The Essential Functions of Adipo-osteogenic Progenitors as the Hematopoietic Stem and Progenitor Cell Niche. (2010)
  • Author(s): Omatsu, T.
  • Journal Title: Immunity Volume: VOL.33 Pages: 387-399
  • Peer Reviewed
• [Journal Article] Bone marrow graft-versus-host disease : early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation. (2010)
  • Author(s): Shono, Y.
  • Journal Title: Blood Volume: VOL.115 Pages: 5401-5411
  • Peer Reviewed
• [Journal Article] Dock 180 is a rac activator that regulates cardiovascular development by acting downstream of CXCR4. (2010)
  • Author(s): Sanematsu, F.
  • Journal Title: Circ.Res. Volume: VOL.107 Pages: 1102-1105
  • Peer Reviewed
• [Presentation] Bone marrow niches controlling behavior of hematopoietic stem and progenitor cells (2012)
  • Author(s): 長澤丘司
  • Organizer: The 21st Hot Spring Harbor Symposium jointly with 9th Global COE international Symposium
  • Place of Presentation: 九州大学(福岡)(招待講演)
  • Year and Date: 2012-01-22
• [Presentation] Adipo-osteogenic progenitors constitute reticular niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): 長澤丘司
  • Organizer: The 23th Korean Sciety of Bone Metabolism Autumn Scientitic Congress
  • Place of Presentation: ソウル(韓国)(招待講演)
  • Year and Date: 2011-11-19
• [Presentation] CXCL12 and reticular niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): 長澤丘司
  • Organizer: 40th Annual Scientific Meeting of the ISEH-Society for Hematology and Stem Cells
  • Place of Presentation: バンクーバー(カナダ)(招待講演)
  • Year and Date: 2011-08-26
• [Presentation] Bone marrow niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): 長澤丘司
  • Organizer: 日本炎症・再生医学会
  • Place of Presentation: 国立京都国際会館(京都府)(招待講演)
  • Year and Date: 2011-06-03
• [Presentation] The chemokine CXCL12 and niches for hematopoietic stem cells and immune cells. (2010)
  • Author(s): T.Nagasawa
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan(招待)
  • Year and Date: 2010-08-24
• [Presentation] The chemokine CXCL12 and bone marrow niches for hematopoietic stem cells (HSCs) and immune cells. (2010)
  • Author(s): T.Nagasawa
  • Organizer: 3rd International Conference on Osteoimmunology
  • Place of Presentation: Fira, Santorini, Greece(招待)
  • Year and Date: 2010-06-21