PREVENTION OF GRAFT-VERSUS-HOST DISEASE BY TARGETING ANTIGEN-PRESENTING CELLS AND BY TOLERANCE INDUCTION
| Project/Area Number |
15591007
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | KYUSHU UNIVERSITY (2004)
Okayama University (2003) |
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Principal Investigator |
TESHIMA Takanori KYUSHU UNIVERSITY, KYUSHU UNIVERSITY HOSPITAL, ASSOCIATE PROFESSOR, 大学病院, 助教授 (40284096)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | GRAFT-VERSUS-HOST DISEASE / α-GALACTOSYLCERAMIDE / NKT CELLS / HEMATOPOIETIC CELL TRANSPLANTATION / DENDRITIC CELLS / IL-4 / TH2 / -galactosylceramide / NKT細胞 / GVHD / 造血幹細胞移植 |
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| Research Abstract |
We first studied to determine the most critical antigen-presenting cells(APCs) in mouse models of GVHD. We found that hostr, but not donor, derived dendritic cells(DCs) alone are sufficient to cause GVHD. In contrast, host-derived B cells atone were not able to induce GVHD in vivo. These results suggest that selective elimination or suppression of host APCs can be a promising strategy to inhibit the induction of GVHD. We also tested whether several irnmunological approaches to induce tolerance can be applied to suppress GVHD again in mouse models of GVHD. We have investigated whether stimulation of host NKT cells could modulate acute graft-versus-host disease(GVHD) in mice. Injection of the synthetic NKT cell ligandα-galactosylceramide(α-GalCer) to recipient mice on day 0 following allogeneic bone marrow transplantation promoted Th2 polarization of donor T cells and a dramatic reduction of serum TNF-a, a critical mediator of GVHD. A single injection of α-GalCer to recipient mice significantly reduced morbidity and mortality of GVHD. However, the same treatment was unable to confer protection against GVHD in NKT cell deficient CD1d knockout (CD1d^<-/->) or IL-4^<-/-> recipient mice or when STAT6^<-/-> mice were used as donors, indicating the critical role of host NKT cells, host production of IL-4,and Th2 cytokine responses mediated by donor T cells on the protective effects of α-GalCer against GVHD. Thus stimulation of host NKT cells through administration of NKT ligand can regulate acute GVHD by inducing Th2 polarization of donor T cells via STAT6-dependent mechanisms and might represent a novel strategy for prevention of GVHD.
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Report
(3 results)
Research Products
(20 results)
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[Journal Article] Role of CXCR3 induced donor T-cell migration in acute GVHD2003
Author(s)
Duffner U, Lu B, Hildebrandt GC, Teshima T, Williams DL, Reddy P, Ordemann R, Clouthier SG, Lowler K, Liu C, Gerard C, Cooke KR, Ferrara JLM
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Journal Title
Experimental Hematology 31・10
Pages: 897-902
Description
「研究成果報告書概要(和文)」より
Related Report
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[Journal Article] Role of CXCR3 induced donor T-cell migration in acute GVHD.2003
Author(s)
Duffner U, Lu B, Hildebrandt GC, Teshima T.Williams DL, Reddy P, Ordemann R, Clouthier SG, Lowler K, Liu C, Gerard C, Cooke KR, Ferrara JLM
-
Journal Title
Experimental Hematology 31(10)
Pages: 897-902
Description
「研究成果報告書概要(欧文)」より
Related Report
-
[Journal Article] Role of CXCR3 induced donor T-cell migration in acute GVHD2003
Author(s)
Duffiner U, Lu B, Hildebrandt GC, Teshima T, Williams DL, Reddy P, Ordemann R, Cloutheir SG, Lowler K, Liu C, Gerard C, Cooke KR, Ferrara JLM
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Journal Title
Experimental Hematology 31・10
Pages: 897-902
Related Report
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[Publications] Ichiba T, Teshima T, Kuick R, Misek D, Liu C, Takada Y, Maeda Y, Reddy P, Williams D, Hanash S, Feriara JLM: "Early changes in gene expression profiles of hepatic GVHD uncovered by ologonucleotide mnicroarrays"Blood. 102. 763-771 (2003)
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[Publications] Duffner U, Lu B, Hildebrandt GC, Teshima T, Williams DL, Reddy P, Ordemann R, Clouthier SG, Lowler K, Liu C, Gerard C, Cooke KR, Ferrara JLM: "Role of CXCR3 induced donor T-cell migration in acute GVHD"Experimental Hematology. 31. 897-902 (2003)
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