Examining a role for histone deacetylase inhibitors as immunosuppressants in organ transplantation

Ellis, Jonathan (2016). Examining a role for histone deacetylase inhibitors as immunosuppressants in organ transplantation. University of Birmingham. M.D.

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Abstract

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 initially assessed a panel of experimental and established HDACis, identifying a novel HDAC6-specific inhibitor (KA1010) to compare with cyclosporin and the pan-HDACi suberoylanilide hydroxamic acid in models of alloreactivity.

Proliferation and 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.
KA1010 displayed superior inhibitory effects on the activation of PBMCs using in vitro models of transplantation. In a one-way MLR, KA1010 (5μM) reduced parent cell proliferation from 92% to 64% (p=0.001). A two-way MLR, adopting IFN-γ production as a marker of alloresponse, resulted in up to 91% reduction. Dose-response curves revealed dose-dependent profiles with a greater potency of HDACis over CyA.

Mice treated with KA1010 displayed no significant features of skin allograft rejection upon histological analysis at 70 days and graft survival of upto 80%. Immunological assessment, revealed a significant increase in 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).

HDAC6 may represent an optimal target for future immunosuppressant therapeutics with a particular role in transplantation. In this thesis, we have demonstrated a superior immunosuppressive effect of KA1010 over both CyA and SAHA, in the models of allotransplantation adopted.

Type of Work:

Thesis (Higher Doctorates > M.D.)

Award Type:

Higher Doctorates > M.D.

Supervisor(s):