title: Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells.
abstract: Histone methylation is thought to be important for regulating Ag-driven T-cell responses. However, little is known about the effect 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 GVHD in mice after allogeneic BM transplantation. DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury. This effect was associated with the ability of DZNep to selectively reduce trimethylation of histone H3 lysine 27, deplete the histone methyltransferase Ezh2 specific to trimethylation of histone H3 lysine 27, and activate proapoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not affect 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 antileukemia activity of donor T cells and did not impair the recovery of hematopoiesis and lymphocytes, leading to significantly improved survival of recipients after allogeneic BM transplantation. 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.
authors: Department of Internal Medicine, University of Michigan, 1500 E Medical Drive, Ann Arbor, MI 48109-5942, USA.
authors: Shan
authors: S
authors: He
authors: Jina
authors: J
authors: Wang
authors: Koji
authors: K
authors: Kato
authors: Fang
authors: F
authors: Xie
authors: Sooryanarayana
authors: S
authors: Varambally
authors: Shin
authors: S
authors: Mineishi
authors: Rork
authors: R
authors: Kuick
authors: Kazuhiro
authors: K
authors: Mochizuki
authors: Yongnian
authors: Y
authors: Liu
authors: Evelyn
authors: E
authors: Nieves
authors: Ram-Shankar
authors: RS
authors: Mani
authors: Arul M
authors: AM
authors: Chinnaiyan
authors: Victor E
authors: VE
authors: Marquez
authors: Yi
authors: Y
authors: Zhang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000517:prevention & control*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007519:Isoantigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D013379:Substrate Specificity / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D007519:Isoantigens; C048460:3-deazaneplanocin; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000241:Adenosine