title: Inhibition of Histone Deacetylase 6 Reveals a Potent Immunosuppressant Effect in Models of Transplantation.
abstract: BACKGROUND
  Current transplant immunosuppression regimens have numerous limitations. Recent evidence suggests histone deacetylase inhibitors (HDACis) may represent a class of drug with immunosuppressive properties. This study compares cyclosporin A (CyA) with the pan-HDACi suberoylanilide hydroxamic acid (SAHA) and a novel HDAC6-specific inhibitor (KA1010) in models of alloreactivity.
  
  
  METHODS
  Proliferation and mixed lymphocyte reaction (MLR)-based assays were used to determine the immunosuppressive effect of compounds, and a murine model of allogeneic skin transplantation was adopted to assess the in vivo effects of HDAC6 inhibition.
  
  
  RESULTS
  KA1010 displayed superior inhibitory effects on the activation of peripheral mononuclear cells using in vitro models of transplantation. In a 1-way MLR, KA1010 (5 μΜ) reduced parent cell proliferation from 92% to 64% (P = 0.001). A 2-way MLR, adopting IFN-γ production as a marker of alloresponse, resulting in up to 91% reduction. Dose-response curves revealed dose-dependent profiles with greater potency of HDACis over CyA (IC50 values of 82.0 nM and 13.4 nM for KA1010 and SAHA).Mice treated with KA1010 displayed no significant features of skin allograft rejection upon histological analysis at 70 days and graft survival of 80% in subjects treated with 160 mg/kg. Immunological assessment, revealed a significant increase in CD4CD25forkhead box P3 regulatory T cells (from 18% to 25%, P = 0.0002) and a corresponding reduction in CD4 T cells (from 58% to 42%, P = 0.0009).
  
  
  CONCLUSIONS
  HDAC6 may represent an optimal target for future immunosuppressant therapeutics with a particular role in transplantation. In this article, we have demonstrated a superior immunosuppressive effect of KA1010 over both CyA and SAHA, in the models of allotransplantation adopted.
authors.affiliation: 1 Department of Renal and Transplant Surgery, University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom.2 Department of Histopathology, University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom.3 Department of Clinical Immunology, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.4 Karus Therapeutics Limited, Abingdon, Oxfordshire, United Kingdom.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ellis
authors.forename: Desley A H
authors.initials: DA
authors.lastname: Neil
authors.forename: Nick G
authors.initials: NG
authors.lastname: Inston
authors.forename: Eric
authors.initials: E
authors.lastname: Jenkinson
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.forename: Peter
authors.initials: P
authors.lastname: Hampson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Shuttleworth
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Ready
authors.forename: Mark
authors.initials: M
authors.lastname: Cobbold
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016038:Skin Transplantation / Q000009:adverse effects*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous; D000077337:Vorinostat
chemical_list: D000631:Aminopyridines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C573415:IFNG protein, human; D007166:Immunosuppressive Agents; C000619491:KA1010; D000077337:Vorinostat; D007371:Interferon-gamma; D016572:Cyclosporine; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases