SAHA, an HDAC Inhibitor, Attenuates Antibody-Mediated Allograft Rejection

Abstract

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. 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. 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. Our data support that SAHA could be a promising immunosuppressive agent with potential beneficial effect on prevention and treatment of AMR.