Inhibition of histone methyltransferase EZH2 ameliorates early acute renal allograft rejection in rats.

Long Li,Tongyu Zhu,Yi Zhang,Jina Wang,Ruiming Rong,Ming Xu

doi:10.1186/s12865-016-0179-3

Abstract

BackgroundAlthough histone methyltransferases EZH2 has been proved to have significant regulatory effect on the immune rejection after hematopoietic stem cell transplantation, its role in solid-organ transplantation remains uncovered. In this study, we investigate whether histone methylation regulation can impact renal allograft rejection in rat models.ResultsAllogeneic rat renal transplantation model (Wistar to Lewis) was established, and the recipients were administrated with EZH2 inhibitor DZNep after transplantation. Renal allografts and peripheral blood were collected on day 5 after transplantation for histological examination and mechanism investigation. We found that inhibition of EZH2 by DZNep after transplantation significantly ameliorated acute rejection (AR), with decreased histological injury and reduced inflammatory infiltration in renal allografts. Attenuation of AR was due to the prohibited activation of alloreactive T cells, the subsequent impaired production of inflammatory cytokines, and also the elevated apoptosis of alloreactive T cells in both renal allografts and periphery. However, inhibition of EZH2 did not increase the regulatory T cells during the AR.ConclusionsDisruption of EZH2 by DZNep suppressed the immune responses of alloreactive T cells and ameliorated AR of renal allografts. This suggests a therapeutic potential of targeting histone methyltransferases EZH2 in treating allograft rejection after solid organ transplantation.

Highlights

Histone methyltransferases Enhancer of Zeste homology 2 (EZH2) has been proved to have significant regulatory effect on the immune rejection after hematopoietic stem cell transplantation, its role in solid-organ transplantation remains uncovered
Inhibition of EZH2 by deazaneplanocin A (DZNep) ameliorated acute renal allograft rejection Rat renal transplantation was performed and the recipients were sacrificed on day 5 after transplantation
In order to confirm the role of EZH2 inhibition by DZNep in renal transplantation, the protein levels of EZH2 were determined by western blot

Summary

Introduction

Histone methyltransferases EZH2 has been proved to have significant regulatory effect on the immune rejection after hematopoietic stem cell transplantation, its role in solid-organ transplantation remains uncovered. The allogeneic T cells are crucial player during the pathogenesis of immune rejection, since it’s the direct mediator of acute cellular rejection, and synergizes the subsequent humoral rejection [1]. We and other investigators previously reported the potential of histone methylation in regulating the expression of genes associated with survival, proliferation and differentiation of alloreactive T cells [6, 8], implying the novel epigenetic approaches capable of targeting a specific set of genes in alloreactive T cells may be useful for controlling T-cell-mediated allograft rejection.

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