| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Research Abstract |
Histone methylation is thought to be important for regulating antigen-driven T cell responses. However,little is known about the impact of modulating histone methylation on inflammatory T cell responses.We demonstrate that in vivo administration of the histone methylation inhibitor 3-deazaneplanocin A (DZNep) arrests ongoing graft-versus-host disease(GVHD)in mice after alloge neic bone marrow transplantation (BMT).DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury.This effect was associated with DZNep's ability to selectively reduce trimethylation of histone H3 lysine 27 (H3K27me3), deplete the histone methyltransferase Ezh2 specific to H3K27me3 and activate pro-apoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not impact the survival of alloantigen-unresponsive T cells in vivo and naive T cells stimulated by IL-2 or IL-7 in vitro. Importantly, inhibition of histone methylation by DZNep treatment in vivo preserved the anti-leukemia activity of donor T cells and did not impair the recovery of hematopoiesis and lymphocytes, leading to significantly improved survival of recipients after allogeneic BMT.Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat ongoing GVHD and other T cell-mediated inflammatory disorders in a broad context.
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