| Project/Area Number |
16K09880
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kansai Medical University |
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Principal Investigator |
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| Research Collaborator |
HOTTA Masaaki
YOSHIMURA Hideaki
KAMBAYASHI Taku
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | GVHD / 制御性T細胞 / GM-CSF / 樹状細胞 / 造血幹細胞移植 / ＧＶＨＤ / Treg |
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| Outline of Final Research Achievements |
Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases, including graft-versus-host disease (GVHD). Granulocyte-macrophage colony stimulating factor (GM-CSF) increases DC number and may promote DC-dependent Treg proliferation. We demonstrate that GM-CSF treatment increases CD4+CD8-DCs, which is associated with Treg expansion. In a mouse chronic GVHD (cGVHD) model, GM-CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both T helper (Th)1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. These data suggest that GM-CSF induces Treg proliferation by expanding CD4+CD8－DCs which in turn regulates alloimmune responses in a cGVHD mouse model. Thus, GM-CSF could be used as a therapeutic DC modulator to induce Treg expansion and inhibit excessive alloimmune responses in immune-related disease.
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| Academic Significance and Societal Importance of the Research Achievements |
Tregの維持・増殖には、IL-2シグナルと樹状細胞(Dendritic cell; DC)のT細胞受容体(T cell receptor; TCR)刺激や副刺激因子からのシグナルが重要な役割を果たす。GM-CSFは同種造血幹細胞移植後のDCサブセットの比率に変化をもたらし、Treg増幅を導くことで慢性GVHDを抑制しうることが明らかになった。ステロイドに抵抗性を示す場合、有効な二次治療が未だ確立されていない慢性GVHDの治療において、GM-CSFを用いた生体内Treg増殖療法は、慢性GVHDの新たな治療選択肢として応用できる可能性を示すことができた。
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