title: SAHA, an HDAC inhibitor, attenuates antibody-mediated allograft rejection.
abstract: BACKGROUND
  Antibody-mediated rejection (AMR) is gaining increasing recognition as a critical causative factor contributing to graft loss in organ transplantation. However, current therapeutic options for prevention and treatment of AMR are very limited and ineffective. The impact of epigenetic modification in B-cell function and its involvement in AMR is still yet to be explored.
  
  
  METHODS
  The impacts of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on isolated murine B-cell viability, proliferation, apoptosis, expression of surface marker, and secretion of immunoglobulin and interleukin-10 were investigated. In vivo, a murine cardiac transplant model was used to evaluate the effect of SAHA on splenic B-cell subsets and on AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells.
  
  
  RESULTS
  SAHA possesses capability to repress B-cell function. Specifically, SAHA is potent to decrease the viability of isolated B cells by inducing apoptosis. SAHA was also found capable of suppressing the expression of B-cell costimulatory molecules and, as a result, addition of SAHA into the cultures attenuated B-cell proliferation and immunoglobulin secretion. In line with these results, administration of SAHA significantly suppressed AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells along with enhanced cardiac allograft survival time. Mechanistic studies revealed that SAHA promotes B-cell secretion of interleukin-10.
  
  
  CONCLUSIONS
  Our data support that SAHA could be a promising immunosuppressive agent with potential beneficial effect on prevention and treatment of AMR.
authors.affiliation: 1 Institute of Organ Transplantation, Changzheng Hospital, Shanghai, China. 2 National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China. 3 Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. 4 Department of Urology, General Hospital of Lanzhou Military Region, Lanzhou, China. 5 Address correspondence to: Prof. Quan-xing Wang, National Key Laboratory of Medical Immunology, Second Military Medical University or Prof. Liming Wang, Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Meng
authors.initials: M
authors.lastname: Guo
authors.forename: Yindong
authors.initials: Y
authors.lastname: Kang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Xueyang
authors.initials: X
authors.lastname: Zheng
authors.forename: Shu
authors.initials: S
authors.lastname: Han
authors.forename: Shangxi
authors.initials: S
authors.lastname: Fu
authors.forename: Shanjuan
authors.initials: S
authors.lastname: Hong
authors.forename: Guoshan
authors.initials: G
authors.lastname: Ding
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Quan-Xing
authors.initials: QX
authors.lastname: Wang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007136:Immunoglobulins / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D007518:Isoantibodies / Q000097:blood*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D000077337:Vorinostat
chemical_list: D015703:Antigens, CD; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; C556062:IL10 protein, mouse; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D007518:Isoantibodies; C064658:RAG-1 protein; D016753:Interleukin-10; D000077337:Vorinostat