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

Abstract

Summary 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.

Inhibiting NFAT5 With KRN2 Mitigates Acute Allograft Rejection in a Murine Heart Transplantation Model

“…Heterotopic cardiac transplantation was performed as described previously. 19 Donor mice (BALB/c or C57BL/6) were anesthetized and operated on to remove the heart. Donor mice (BALB/c or C57BL/6) were anesthetized, and the ascending aorta and pulmonary artery of the donor were anastomosed with the recipient's abdominal aorta and inferior vena cava by end-to-side anastomosis in the recipient mouse's abdominal cavity.…”

M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection

“…Treated with recombinant IL-23, unpolarized mouse peritoneal macrophages represent significantly increased production of IL-17A and IFN-γ via STAT3-RORγ T pathways, but not M1/M2 related cytokines, and neither polarized M1 nor M2-like macrophages can convert to such an IL-17/IFN-γ high-producing subset: M(IL-23) (15). Thus, M(IL-23) is likely to be defined as a new macrophage subpopulation and is worth discussing since alloreactive production of IL-17/IFN-γ is closely related to allograft rejection (16).…”