Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Transpl Int. 2021 Mar;34(3):561-571. doi: 10.1111/tri.13809. Epub 2021 Feb 26.
Acute allografts rejection is the most important factor causing allograft disability for many patients undergoing organ transplantation. PJ34, which is a specific inhibitor of poly(ADP-ribose) polymerase 1, is involved in immune regulation, may be effective in preventing acute cardiac rejection. We performed the models of abdominal heterotopic heart transplantation. PJ34 was injected intraperitoneally daily (20 mg/kg/day) starting the day after surgery. The severity of rejection was determined by histology. The mRNA expression levels of cytokines and transcription factors in the grafts were measured by quantitative polymerase chain reaction (qPCR). The proportion and number of T-cell subpopulations in the spleens were analyzed by flow cytometry. In vitro, the effect of PJ34 on allogeneic responses was investigated. We found treatment with PJ34 prolonged allograft survival compared with normal saline treatment. Compared with the control group, PJ34 treatment reduced the proportion of CD4 IFN-γ and CD4 IL-17A cells and increased the percent of CD4 IL-4 and CD4 Foxp3 cells in the spleens. In vitro, PJ34 treatment significantly inhibited the mRNA levels of IFN-γ and IL-17A and promoted the mRNA levels of TGF-β and FOXP-3 in activated CD4 T cells. Modulating the CD4 T lymphocyte response with PJ34 could attenuate acute allografts rejection after murine heart transplantation. These findings indicate that PARP1 may be a promising therapeutic target to attenuate acute cardiac allograft rejection.
急性同种异体移植物排斥是导致许多接受器官移植的患者移植物功能障碍的最重要因素。PJ34 是聚（ADP-核糖）聚合酶 1 的特异性抑制剂，参与免疫调节，可能有效预防急性心脏排斥反应。我们进行了腹部异位心脏移植模型。术后第 1 天开始每天腹腔内注射 PJ34（20mg/kg/天）。通过组织学确定排斥反应的严重程度。通过定量聚合酶链反应（qPCR）测量移植物中细胞因子和转录因子的 mRNA 表达水平。通过流式细胞术分析脾中 T 细胞亚群的比例和数量。在体外，研究了 PJ34 对同种异体反应的影响。我们发现，与生理盐水治疗相比，PJ34 治疗可延长移植物存活时间。与对照组相比，PJ34 治疗降低了脾中 CD4 IFN-γ和 CD4 IL-17A 细胞的比例，并增加了 CD4 IL-4 和 CD4 Foxp3 细胞的比例。在体外，PJ34 治疗显著抑制激活的 CD4 T 细胞中 IFN-γ和 IL-17A 的 mRNA 水平，并促进 TGF-β和 FOXP-3 的 mRNA 水平。用 PJ34 调节 CD4 T 淋巴细胞反应可减轻小鼠心脏移植后的急性同种异体移植物排斥反应。这些发现表明 PARP1 可能是减轻急性心脏同种异体移植物排斥反应的有前途的治疗靶点。
