| Project/Area Number |
21790973
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pediatrics
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| Research Institution | 国立病院機構金沢医療センター (2010)
Department of Clinical Research, National Hospital Organization Kanazawa Medical Center (2009) |
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Principal Investigator |
前馬 秀昭 国立病院機構金沢医療センター, 臨床研究部, 小児科医師 (10419335)
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| Project Period (FY) |
2009 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2009: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | GVHD / 制御性樹状細胞 / 造血幹細胞移植 / PUVA療法 / 移植片対宿主病 |
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| Research Abstract |
Bone marrow-derived cultured DCs acquired tolerogenicity by PUVA (psoralen+UVA) treatment in mice. In MLR assays, strong tolerogenicity was observed when adding PUVA-DCs generated from the same strain of stimulator cells, or responder cells, or even from third party strain into MLR mixture. That is, the PUVA-treated DCs have tolerogenic function in a MHC-independent manner, in part, due to the reduced expression levels of CD80 and CD86. To clarify the mechanisms of how PUVA-treated DCs induce tolerogenicity in further detail, we performed MLR with the addition of neutralizing antibodies against IL-10 or TGF-b1 or both. Neutralization of immunosuppressive cytokines had no effects on MLR. We then showed that cell-to-cell contact between PUVA-DCs and alloreactive T-cells was needed to mediate the regulatory effect by transwell experiment. Next we compared the expression of the indoleamine 2,3-dioxygenase (IDO), which induces T-cell anergy by tryptophan depletion and by the production of metabolic byproducts collectively known as kynurenines, by real-time PCR between PUVA-DCs and BM-DCs. An increase IDO gene transcription level was observed in PUVA-DCs about 5 times more than in BM-DCs (p<0.01). In conclusion, PUVA-DCs acquired regulatory function in a MHC-independent manner by upregulation of IDO. Infusion of PUVA-treated DCs could have a great potential to treat lethal acute GVHD in clinical settings.
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