PJ34, a PARP1 inhibitor, attenuates acute allograft rejection after murine heart transplantation via regulating the CD4+ T lymphocyte response

Abstract

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.

Keywords: CD4+ T lymphocyte; PARP1 inhibitor; PJ34; acute allograft rejection; heart transplantation.