| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Graft-versus-host disease (GVHD) is the most significant clinical problem that arises after allogeneic hematopoietic cell transplantation. Chemokines induced during the development of GVHD promote T-cell migration into GVHD target organs and contribute to severity of GVHD. Therefore, we analyzed the expression of chemokines in GVHD target organs in an animal model and tried the therapy through chemokine antagonists and their receptors.
In this study, we used acute GVHD model mouse: C57BL/6 (donor) and (C57BL/6 X DBA/2)F1 (B6D2F1) (recipient). The B6D2F1 mice were treated by 13 Gy irradiation. During the development of GVHD, expressions of Th1-associated chemokines (Mig/CXCL9 and IP-10/CXCL10), Th2-associated chemokines (TARC and MDC), MIP-1α and-1β, RANTES, and KC were increased in liver. In contrast, Th1-associated chemokines, MIP-lα and-β, MCP-1 and-3, and LTN were increased in gut. From this finding, high levels of expression of Th1-associated chemokines and their receptor CXCR3 were observed in the liver and intestines of GVHD-induced recipient mice. Next, we tried the treatment of acute GVHD by using IP-10 antagonist. Consiquently, IP-10 antagonist ameliorated the damage significantly in liver and gut, compared with control mice.
Recipient mice that had undergone transfer of CD4^+CD25^+Foxp3^+ CXCR3-transfected T cells (CXCR3-Treg cells) showed significant amelioration of GVHD changes in the liver and intestines in comparison with recipient mice that had received CD4^+CD25^+Foxp3^+ T cells (Treg cells). This was due to more pronounced migration of CXCR3-Treg cells and their localization for a longer time in TM-associated chemokine-expressing organs, resulting in stronger suppressive activity. Thus we succeeded in preparing chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression upon accumulation in target organs. This method may provide a new therapeutic approach for organ damage in acute GVHD.
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