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PARP-1 inhibitor-AG14361 suppresses acute allograft rejection via stabilizing CD4+FoxP3+ regulatory T cells

Acute allograft rejection is the most common complication in organ transplantation leading to organ loss. Treg cells play an important role in preventing acute rejection, but they are unstable and easily lose function. Poly(ADP-ribose) polymerase 1(PARP-1) is involved in the differentiation stabilization of Treg cells, it has been suggested that PARP-1 inhibition could prevent acute rejection and prolong allograft survival. This study investigated AG14361 effects on acute allograft rejection. We used a fully MHC-mismatched murine heart transplantation model to compare the effect of PARP-1 inhibitor-AG14361 on alloimmunity to the control. Mice treated with PARP-1 inhibitors showed a longer median survival time of allografts (MS14 compared with the control group, MST was 8 days, and AG14361 was 6 days, P = 0.019). The combination of sirolimus and AG14361 significantly delayed allograft MST (AG14361 + sirolimus for 30 days, sirolimus for 16 days, P = 0.002). AG14361 markedly augmented the number of the CD25+FoxP3+ Treg cells in the graft and periphery. In addition, it could enhance the suppressive function of Treg cells by upregulating the level of CTLA-4, PD-1 and ICOS. In vivo, the Treg/Th17 ratio increased significantly in the AG14351 group compared to the control. In the combination with sirolimus treatment, AG14361 promoted the long-term allograft survival. Our results highlight novel effects of a PARP-1 inhibitor. PARP-1 inhibitor AG14361 may be a promising agent to attenuate acute allograft rejection as it can maintain the number and function of Treg cells in allografts.

 

Comments：

This study investigated the potential of a PARP-1 inhibitor, AG14361, to prevent acute allograft rejection in a murine heart transplantation model. The results showed that treatment with AG14361 increased the median survival time of allografts, compared to the control group. In addition, the combination of AG14361 and sirolimus significantly delayed allograft median survival time compared to sirolimus alone.

The study also found that AG14361 increased the number of CD25+FoxP3+ Treg cells in both the graft and periphery, and enhanced the suppressive function of Treg cells by upregulating the levels of CTLA-4, PD-1, and ICOS. Moreover, the Treg/Th17 ratio increased significantly in the AG14361 group compared to the control group in vivo.

These findings suggest that AG14361 may be a promising agent for attenuating acute allograft rejection by maintaining the number and function of Treg cells in allografts. However, further studies are needed to investigate the potential side effects and safety of using AG14361 in organ transplantation.

 

Related Products

Cat.No. Product Name Information
S2178 AG-14361 AG14361 is a potent inhibitor of PARP1 with Ki of <5 nM in a cell-free assay. It is at least 1000-fold more potent than the benzamides.

Related Targets

PARP