Triptolide inhibits CD4+ memory T cell-mediated acute rejection and prolongs cardiac allograft survival in mice

Abstract

There have been numerous investigations into the immunosuppressive effects of triptolide; however, its inhibitory effects on memory T cells remain to be elucidated. Using a cluster of differentiation (CD)4+ memory T-cell transfer model, the aim of the present study was to determine the inhibitory effects of triptolide on CD4+ memory T cell-mediated acute rejection and to determine the potential underlying mechanisms. At 4 weeks after skin transplantation, mouse cervical heart transplantation was performed following the transfer of CD4+ memory T cells. Mice were divided into two groups: A Control [normal saline, 30 ml/kg/day; intraperitoneal injection (ip)] and a triptolide group (triptolide, 3 mg/kg/day; ip). Graft survival, pathological examination and the corresponding International Society for Heart & Lung Transplantation (ISHLT) scores were assessed 5 days following heart transplantation, and levels of interleukin (IL)-2, interferon-γ (IFN-γ), IL-10 and transforming growth factor β1 (TGF-β1) in cardiac grafts and peripheral blood were assessed using reverse transcription-quantitative polymerase chain reaction and ELISA. The duration of cardiac graft survival in the triptolide group was significantly increased compared with the control group (14.3±0.4 vs. 5.3±0.2 days; P<0.001). Further pathological examinations revealed that the infiltration of inflammatory cells and myocardial damage in the cardiac grafts was notably reduced by triptolide, and the corresponding ISHLT scores in the triptolide group were significantly lower than those of the control group (grade 2.08±0.15 vs. 3.67±0.17; P<0.001). In addition, triptolide was able to significantly reduce IL-2 and IFN-γ secretion (P<0.01), significantly increase TGF-β1 secretion in the cardiac grafts and peripheral blood (P<0.01) and increase IL-10 secretion in the cardiac grafts. Therefore, the present study suggests that triptolide inhibits CD4+ memory T cell-mediated acute rejection and prolongs cardiac allograft survival in mice. This effect may be mediated by the inhibition of cytokine secretion by type 1 T helper cells and promotion of regulatory T cell proliferation.

Triptolide Attenuates Transplant Vasculopathy Through Multiple Pathways

“…Triptolide inhibited intimal thickening by suppressing the IFN-γ axis. Numerous studies had reported that triptolide inhibited the proliferation and activity of T lymphocytes (16,29), and prevented the production of IFN-γ in some disease models (19,30). However, no study investigated the effect of triptolide on the IFN-γ axis in attenuating TV.…”

“…Triptolide is a structurally unique diterpene triepoxide and a principal bioactive component of the Chinese traditional medicine Tripterygium wilfordii Hook F, which is broadly used in clinic due to its strong immunosuppressive and anti-proliferative properties (14,15). Triptolide has been proved to suppress the proliferation and activity of T lymphocytes and macrophages (16,17), and is a strong inhibitor of IFN-γ signaling pathway in tumors and inflammation-related diseases (18,19). However, there are few studies exploring its effects on antibodies.…”

Investigation of hub genes and immune status in heart transplant rejection using endomyocardial biopsies

“…T cell‒mediated rejection and ABMR have emerged as major risk factors for limiting heart allograft survival 19‐21 . However, the differences in gene expression and immune status of rejection and stable heart graft samples are still unknown.…”

“…T cell-mediated rejection and ABMR have emerged as major risk factors for limiting heart allograft survival. [19][20][21] However, the differences in gene expression and immune status of rejection and stable heart graft samples are still unknown. Bioinformatics analysis identified a total of 740 and 231 DEGs in the TCMR and ABMR groups, respectively.…”

Effect of Inhibition of the JAK2/STAT3 Signaling Pathway on the Th17/IL-17 Axis in Acute Cellular Rejection After Heart Transplantation in Mice

“…Myocardial tissue of the donor heart in each group was fixed in 4% formaldehyde solution for 24 hours to prepare paraffin sections with a thickness of 4 µm, which were stained with hematoxylin and eosin (H&E) and observed under an optical microscope. Because there is no biopsy standard for acute cellular rejection of mice myocardial tissue, according to related research, 18 the ratings of this study were based on the heart transplant rejection standard revised by ISHT in 2004 19 (Table 1 ).…”