Inhibition of Histone Deacetylase 6 Reveals a Potent Immunosuppressant Effect in Models of Transplantation

Autor: Andrew R. Ready, E. J. Jenkinson, Mark T. Drayson, Mark Cobbold, Jonathan D. Ellis, Nick G. Inston, Desley Neil, Peter Hampson, Stephen J. Shuttleworth
Rok vydání: 2016
Předmět:
Graft Rejection
Male
0301 basic medicine
Time Factors
medicine.medical_treatment
Aminopyridines
Pharmacology
Histone Deacetylase 6
Hydroxamic Acids
Lymphocyte Activation
T-Lymphocytes
Regulatory
Peripheral blood mononuclear cell
Histone Deacetylases
Article
Interferon-gamma
03 medical and health sciences
0302 clinical medicine
In vivo
Cyclosporin a
medicine
Animals
Humans
Transplantation
Homologous
Potency
Molecular Targeted Therapy
Cells
Cultured
Cell Proliferation
Skin
Mice
Inbred BALB C
Vorinostat
Transplantation
Dose-Response Relationship
Drug
Chemistry
Graft Survival
Skin Transplantation
Mixed lymphocyte reaction
Histone Deacetylase Inhibitors
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
030220 oncology & carcinogenesis
Cyclosporine
Leukocytes
Mononuclear
Histone deacetylase
Lymphocyte Culture Test
Mixed
Immunosuppressive Agents
Signal Transduction
Allotransplantation
Zdroj: Transplantation. 100:1667-1674
ISSN: 0041-1337
DOI: 10.1097/tp.0000000000001208
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: