title: Modulation of allogeneic CD8+ T-cell response by DZNep controls GVHD while preserving hematopoietic chimerism.
abstract: BACKGROUND
  Allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with solid-organ transplantation is a feasible method to achieve long-lasting organ allograft tolerance through the induction of hematopoietic chimerism in recipients. However, the allo-HSCT engraftment puts recipients at risk of life-threatening graft-versus-host disease (GVHD). Novel immunomodulatory approaches are required to effectively control GVHD while preserving the status of hematopoietic chimerism. We have reported that histone methylation inhibitor 3-deazaneplanocin A (DZNep) can control ongoing GVHD in mice by selectively inducing apoptosis of alloreactive effector T cells.
  
  
  METHODS
  Using donor-derived CD8 T cell-mediated mouse GVHD model, we further investigated the effect of in vivo administration of DZNep on allogeneic CD8 T cell response and the hematopoietic chimerism in recipients.
  
  
  RESULTS
  We found that DZNep delayed the in vivo proliferation of donor-derived alloreactive CD8 T cells and also reduced the interleukin-2 production by these T cells. Moreover, DZNep treatment resulted in a significant decrease of interferon-γ, tumor necrosis factor-α, granzyme B, TRAIL, and Fas ligand expressing donor-derived CD8 T cells, suggesting a multilevel modulation role on T-cell survival and effect in vivo. Notably, DZNep treatment did not hamper the generation of hematopoietic chimerism in recipients.
  
  
  CONCLUSIONS
  These findings suggest that modulation of histone methylation through DZNep may be a potential strategy for the induction of hematopoietic chimerism to achieve donor-specific organ allograft tolerance through donor allo-HSCT combined with solid-organ transplantation.
authors.affiliation: 1 Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China. 2 Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
authors.forename: Jina
authors.initials: J
authors.lastname: Wang
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Ruiming
authors.initials: R
authors.lastname: Rong
authors.forename: Tongyu
authors.initials: T
authors.lastname: Zhu
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053804:Granzymes / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008745:Methylation; D051379:Mice; D008809:Mice, Inbred C3H; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013997:Time Factors; D018183:Transplantation Chimera; D023001:Transplantation Tolerance / Q000187:drug effects; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006657:Histones; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C048460:3-deazaneplanocin; D007371:Interferon-gamma; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D053804:Granzymes; C509214:Gzmb protein, mouse; D000241:Adenosine
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Sep;287(3):G592-8
references.pmid: 15087281
references.citation: Am J Transplant. 2012 May;12(5):1133-45
references.pmid: 22405058
references.citation: Annu Rev Immunol. 2007;25:139-70
references.pmid: 17129175
references.citation: Blood. 2012 Feb 2;119(5):1274-82
references.pmid: 22117046
references.citation: Nat Med. 2005 Dec;11(12):1299-305
references.pmid: 16288282
references.citation: Transplantation. 1998 Jul 15;66(1):96-102
references.pmid: 9679828
references.citation: Am J Kidney Dis. 2006 Apr;47(4 Suppl 2):S37-51
references.pmid: 16567240
references.citation: Nat Med. 2005 Nov;11(11):1244-9
references.pmid: 16227991
references.citation: Transplantation. 2013 Jan 15;95(1):155-60
references.pmid: 23263505
references.citation: N Engl J Med. 2002 Feb 21;346(8):580-90
references.pmid: 11856798
references.citation: Am J Transplant. 2006 Sep;6(9):2121-33
references.pmid: 16796719
references.citation: Lancet. 2009 May 2;373(9674):1550-61
references.pmid: 19282026
references.citation: Blood. 2004 May 15;103(10):3986-8
references.pmid: 14764530
references.citation: J Clin Invest. 2002 May;109(10):1335-44
references.pmid: 12021249
references.citation: Antiviral Res. 1993 Jul;21(3):197-216
references.pmid: 8215298
references.citation: Antimicrob Agents Chemother. 1989 Aug;33(8):1291-7
references.pmid: 2552906
references.citation: Immunity. 2001 Apr;14(4):417-24
references.pmid: 11336687
references.citation: Int J Cancer. 2006 Sep 15;119(6):1377-82
references.pmid: 16642465
references.citation: Am J Transplant. 2004 Mar;4(3):378-83
references.pmid: 14961990
references.citation: Breast Cancer Res. 2009;11(4):R63
references.pmid: 19709408
references.citation: Apoptosis. 2003 Jun;8(3):237-49
references.pmid: 12766484
references.citation: Genes Dev. 2007 May 1;21(9):1050-63
references.pmid: 17437993
references.citation: Transplantation. 1996 Aug 15;62(3):380-7
references.pmid: 8779687
references.citation: Clin Pharmacol Ther. 2013 Jan;93(1):36-45
references.pmid: 23212110
references.citation: N Engl J Med. 2008 Jan 24;358(4):362-8
references.pmid: 18216356
references.citation: Mol Cancer Ther. 2009 Jun;8(6):1579-88
references.pmid: 19509260
references.citation: Cancer Res. 2009 Dec 15;69(24):9211-8
references.pmid: 19934320
references.citation: N Engl J Med. 2003 Sep 4;349(10):931-40
references.pmid: 12954741
references.citation: Nat Rev Immunol. 2007 May;7(5):340-52
references.pmid: 17438575
references.citation: Adv Immunol. 2006;90:133-73
references.pmid: 16730263
references.citation: Sci Transl Med. 2012 Mar 7;4(124):124ra28
references.pmid: 22399264
references.citation: Immunol Rev. 1997 Jun;157:61-72
references.pmid: 9255622
references.citation: N Engl J Med. 1981 Jun 18;304(25):1529-33
references.pmid: 7015133
references.citation: Blood. 2009 Sep 24;114(13):2733-43
references.pmid: 19638619
references.citation: Am J Transplant. 2003 Feb;3(2):178-85
references.pmid: 12603213
references.citation: N Engl J Med. 2008 Jan 24;358(4):353-61
references.pmid: 18216355
references.citation: Transplantation. 2013 Jan 15;95(1):169-76
references.pmid: 23222893