Effect of a New Immunosuppressant Histon Deacetylase (HDAC) Inhibitor FR276457 in a Rat Cardiac Transplant Model

Abstract

Histone deacetylase (HDAC) is a known modulator of gene transcription, and the immunosuppressive activity of HDAC inhibitors has been demonstrated in recent several reports. In this study, the HDAC inhibitor FR276457, a hydroxamic derivative, was found to have a similar inhibitory effect on all mammalian HDACs tested, but no isozyme selectivity. Both FR276457 and tacrolimus exerted an immunosuppressive effect on in vitro rat splenocyte proliferation stimulated with Concanavalin A. Next, the effect of FR276457 on allograft rejection when administered either as a monotherapy or in combination with tacrolimus was investigated in a rat heterotopic cardiac transplant model. Orally administered FR276457 prolonged the median survival times (MST) of the transplanted grafts in the vehicle group from 6 d to 17 or 21 d at doses of 20 or 40 mg/kg, respectively. Histopathological analysis showed the structures of the myocardium were not affected, but interstitial cellular infiltration could not be suppressed completely. Tacrolimus (0.032 mg/kg) prolonged allograft MST to 16 d. FR276457, when combined with tacrolimus, prevented allograft rejection at a dose lower than that of the monotherapy. The combination dose prolonged the MST in the groups treated with 10 and 20 mg/kg to Ͼ28 d, and cellular infiltration was suppressed completely. In conclusion, this study demonstrated that the oral administration of HDAC inhibitor FR276457 can prevent allograft rejection as a monotherapy, and has additive or synergistic effects when combined with tacrolimus.

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

“…Previous studies have demonstrated that HDAC is also actively involved in some inflammatory diseases, 34,35 making these agents hold promise as immunomodulatory drugs. HDACis, such as FR276457 and TSA, have been reported to prolong the median survival time of the transplanted grafts in a rodent animal model as a monotherapy, and even more effective in combination with FK506 or rapamycin, 23,36 which is consistent with our observation in the current study. Obviously, a combination of SAHA and FK506 is more effective than either of them alone in the prevention of allograft rejection, which lead us to explore the pharmacological mechanism of SAHA.…”

Protein Acetylation in the Cardiorenal Axis

“…111 Coadministration of TSA with subtherapeutic doses of rapamycin for 14 days after transplant boosted regulatory T-cell function, induced allograft tolerance and dramatically improved survival in mouse cardiac and pancreatic islet allograft models. 84 Although similar results have been reported with other panHDACis, 99,112,113 class I-selective HDACis do not appear to augment regulatory T-cell function, 85 turning attention to the role of HDAC6 in this process. It will be interesting to determine whether induction of regulatory T cells contributes to efficacy of HDACis in the settings of heart and renal failure.…”

Histone deacetylases as targets for treatment of multiple diseases

“…Tao and Hancock [85] have reported that HDAC inhibition promoted the generation of T reg -cells and enhanced their functions. In addition, administration of FR276457, a hydroxamic derivative, can inhibit T-cell proliferation and prolong allograft survival, thereby exhibiting marked immunosuppressive effects in a rat heterotopic cardiac transplant model [86] and in a canine renal transplant model [87]. …”