2003 Fiscal Year Final Research Report Summary
Development of a new cell therapy by adoptive transfer of regulatory T cells to induce immunological tolerance for the transplanted liver
| Project/Area Number |
14570455
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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 |
Gastroenterology
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| Research Institution | NIIGATA UNIVERSITY |
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Principal Investigator |
ICHIDA Takafumi NIIGATA UNIVERSITY, Medical and Dental Hospital, Associate Professor, 医歯学総合病院, 助教授 (00126509)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGIWA Satoshi NIIGATA UNIVERSITY, Medical and Dental Hospital, Clinical Staff, 医歯学総合病院, 医員 (10419327)
WATANABE Hisami University of the Ryukyu, Center of Molecular Biosciences, Professor, 遺伝子実験センター, 教授 (50143756)
MATSUDA Yasunobu NIIGATA UNIVERSITY, Medical and Dental Hospital, Assistant, 医歯学総合病院, 助手 (40334669)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Regulatory T cells / Immunological tolerance / Liver transplantation / Cell therapy |
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| Research Abstract |
(1)Generation of human regulatory CD4^+CD25^+ T cells
We confirmed that naive CD4^+ cells stimulated with alloantigens in the presence of TGF-β(transforming growth factor-β) differentiate into suppressor cells with a phenotype and functional properties similar if not identical with natural regulatory CD4^+CD25^+ T cells. We also studied the regulatory properties of other cytokines, separately or together with TGF-β, on CD4^+CD25^+ T cells generated by allo-stimulation. Although it has been reported that CD4^+ cells become regulatory T cells ('Tr1 cells') when repeatedly stimulated with IL-10,IL-10 inhibited CD25 expression on CD4^+* cells. Moreover, when naive CD4^+ cells were stimulated with alloantigens in the presence of both IL-10 and TGF-β,IL-10 inhibited the effect of TGF-β on the generation of CD4^+CD25^+ T cells.
(2)Generation of murine regulatory CD4^+CD25^+ T cells
We found that treatment of murine alio-activated CD4^+ T cells with TGF-β and IL-2 also enhanced expression of CD25 and enabled these cells to develop potent suppressive activity. We are planning to use those CD4^+CD25^+ T cells generated ex vivo in skin transplantation model to examine whether transfer of those cells can prevent graft rejection.
(3)CD4^+CD25^+ T cells in the human liver
We also investigated CD4^+CD25^+ T cells in human livers. Although the proportion of CD4^+CD25^+ T cells in the liver was lower than in the peripheral blood, we found a significant increase of CD4^+CD25^+ T cells in the marginal regions of hepatocellular carcinoma(HCC), but not in unaffected areas of the liver. CD4^+CD25^+ T cells isolated from peri-tumor regions of HCC displayed phenotype markers characteristic of regulatory T cells, and inhibited autologous CD8^+ cell proliferation. Our results suggest that CD4^+*CD25^+ T cells in the peri-tumor region of HCC inhibit the generation of tumor-specific CD8^+ cytotoxic T cell activity and, thereby, contribute to the progression of HCC.
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