The study of the mechanisms of immunomodulatory function of mesenchymal stem cells.

• Project/Area Number: 22790918
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: TATARA Raine 自治医科大学, 医学部, 助教 (90570268)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 間葉系幹細胞 / 同種骨髄移植 / 移植片対宿主病(GVHD) / Th17 / 制御性T細胞 / GVHD / Th17細胞

Research Abstract

Mesenchymal stem cells(MSCs) possess an immunomodulatory function and show promise as a cell therapy for graft-versus-host disease(GVHD). But the molecular mechanism(s) underlying immunomodulation by MSCs has not been fully established. Th17 is a recently recognized differentiation category, in which CD4 cells produce IL-17, and regulatory T cells(Treg) are another newly recognized differentiation category, in which CD4 T cells have high levels of Foxp3 expression and suppress T cell proliferation. These two differentiations are thought in a reciprocal relationship. While the role of Th17 in GVHD is still controversial, some investigators reported that Th17 has aggravating effects on GVHD. Treg has been reported to suppress GVHD in a mouse model. To elucidate the molecular mechanism(s) of the immunomodulatory function of MSCs, we herein sought to identify the effects of MSCs on these relatively new T cell differentiations. MSCs inhibited Th17 differentiation even in conditions in which T cell growth was not completely inhibited. Interestingly, an inhibitor of prostaglandin production, indomethacin, and an inhibitor of IDO, 1-methyltryptophan(1-MT), partially restored Th17 differentiation. These results suggest that PGE2 and depletion of tryptophan mediate inhibitory effects of MSCs on Th17.On the other hand, Treg differentiation was not significantly enhanced by MSCs. The mechanisms by which IDO and PGE2 regulate these differentiations are unknown.

Research Products

• [Journal Article] Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation (2011)
  • Author(s): Tatara R, Ozaki K, Kikuchi Y, Hatanaka K, Oh I, Meguro A, Matsu H, Sato K, Ozawa K.
  • Journal Title: Cytotherapy Volume: 13 Issue: 6 Pages: 686-694
  • DOI: 10.3109/14653249.2010.542456
  • Peer Reviewed
• [Journal Article] Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells (2011)
  • Author(s): Meguro A, Ozaki K, Hatanaka K, Oh I, Sudo K, Ohmori T, Matsu H, Tatara., Sato K, Sakata Y, Nakae S, Leonard W J, and Ozawa K
  • Journal Title: Bone Marrow Transplant Volume: 46巻 Issue: 12 Pages: 1557-1565
  • DOI: 10.1038/bmt.2010.342
  • Peer Reviewed
• [Journal Article] AA amyloidosis associated withmacroglobulinemia (2010)
  • Author(s): Tatara, R., Nagai, T., Kobayashi, H., Hatano,K., Suzuki, T., Muroi, K., and Ozawa, K
  • Journal Title: (Letter) Int J Hematol Volume: 92 Issue: 4 Pages: 675-677
  • DOI: 10.1007/s12185-010-0700-z
  • NAID: 10027674199
  • Peer Reviewed
• [Journal Article] Altered effector CD4+T cell function in IL-21R-/-CD4+T cell-mediated graft-versus-host disease (2010)
  • Author(s): Oh I, Ozaki K, Meguro A, Hatanaka K, Kadowaki M, Matsu H, Tatara R, Sato K, Iwakura Y, Nakae S, Sudo K, Teshima T, Leonard WJ, Ozawa K.
  • Journal Title: J Immunol Volume: 185 Pages: 1920-1926
• [Journal Article] IL-21 is critical for GVHD in a mouse model (2010)
  • Author(s): Meguro A, Ozaki K, Oh I, Hatanaka K, Matsu H, Tatara R, Sato K, Leonard WJ, Ozawa K.
  • Journal Title: Bone Marrow Transplant Volume: 45 Issue: 4 Pages: 723-729
  • DOI: 10.1038/bmt.2009.223
• [Presentation] Mesenchymal stem cell mediated suppression of Th17 differentiation through PGE2 and IDO production (2010)
  • Author(s): 多々良礼音
  • Organizer: 日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2010-09-24
• [Presentation] マウス間葉系幹細胞によるTh17分化の抑制:PGE2とIDOを介したメカニズム
  • Author(s): 多々良礼音、尾崎勝俊、菊池裕二、畑中恵子、翁家国、目黒明子、松春子、佐藤一也、永井正、室井一男、小澤敬也
  • Organizer: 第74回日本血液学会学術集会
• [Presentation] Mesenchymal Stem Cells Inhibit Th17 Differentiation through indoleamine-2, 3-dioxygenase(IDO) and PGE2 Production
  • Author(s): 多々良礼音、尾崎勝俊、菊池裕二、畑中恵子、翁家国、目黒明子、松春子、佐藤一也、永井正、室井一男、小澤敬也
  • Organizer: 第16回日本遺伝子治療学会年次学術集会