Triptolide Attenuates Transplant Vasculopathy Through Multiple Pathways

Abstract

Transplant vasculopathy (TV), a hallmark of chronic allograft rejection, is the primary cause of allograft loss after organ transplantation. Because multiple mechanisms are involved in TV pathogenesis, effective therapy for it remains elusive. Here, we identify the role of triptolide, which has a wide spectrum of immuno-suppressive activities, in inhibiting TV development. Murine aortic transplants models were constructed and divided into triptolide-treated and untreated groups. We found that triptolide significantly alleviated intima thickening of allografts by inhibiting multiple pathways. Triptolide significantly reduced infiltration of T lymphocytes and macrophages and inhibited the levels of pro-inflammatory (TNF-α, IL-2, and IL-6) and pro-fibrotic factors (TGF-β, α-SMA, and MMP-9) in the graft. Additionally, triptolide significantly decreased the numbers of IFN-γ-producing T lymphocytes, as well as the expression of IFN-γ and IFN-γ-inducing factor (CXCL9 and CXCL10) in recipient. Moreover, triptolide decreased the numbers of B lymphocytes and plasma cells, as well as the levels of donor specific antibodies (DSAs) in recipient. Furthermore, triptolide not only inhibited vascular smooth muscle cell (VSMC) viability and promoted VSMC apoptosis but also significantly inhibited VSMC migration in vitro. These results emphasize the efficacy of triptolide in inhibiting TV development and provide a basis for developing new treatments to prevent TV-related complications and improve the long-term survival of transplant recipients.

Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy

“…Serum was diluted 20 times with PBS and co-cultivated with the splenocytes (5 × 10 5 cells per well) obtained from the BALB/c at 37°C for 30 min, followed by staining with both anti-IgG-PE and anti-IgM-PE antibodies. The levels of DSA were measured by flow cytometry and presented as mean fluorescence intensity (MFI) ( 4 ).…”

“…Although re-transplantation is an available option, currently there is no alternative novel therapy for the prevention of CAV. Therefore, CAV is considered an urgent and serious problem that needs to be solved in transplantation ( 4 ).…”

Synthetic VSMCs induce BBB disruption mediated by MYPT1 in ischemic stroke

“…In addition, the changes in MYPT1, α-SMA, SM22α, and calponin protein expression were confirmed in cortical arterioles in MYPT1 SMKO mice after MCAO ( Figures 3 F and 3G). Furthermore, to evaluate the switching of VSMCs to the synthetic phenotype, we measured the levels of the main cytokines secreted by HBVSMCs, including IL-8, IL-1β, IL-6, IL-10, TNF-α, and IL-12p70, as reported previously ( Shi et al., 2020 ; Luo et al., 2020 ). In the OGD/R models, although the levels of both IL-8 and IL-6 in the supernatant of HBVSMCs were in high levels, as determined by the CBA Inflammation Kit, IL-6 was the only cytokine secreted by MYPT1-deficient HBVSMCs that was upregulated ( Figure 3 E).…”

“…In many vascular disorders, synthetic VSMCs were proven to be detrimental to vascular integrity by synthesizing and secreting proinflammatory factors and matrix proteins, such as IL-6, TNF-α, IL-8, IL-1β, IL-10, and MCP-1 ( Shen et al., 2019 ). In our study, to evaluate the phenotype switching of synthetic VSMCs and explore the key cytokines, we measured the levels of the main cytokines as reported previously ( Shi et al., 2020 ; Luo et al., 2020 ). In the OGD/R models, we found that in these cytokines, only IL-8 and IL-6 in the supernatant of HBVSMCs were in high levels.…”

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

“…In spite of progresses in immunosuppressive therapy, long-term success of allogeneic organ transplantation is limited by the establishment of allograft vasculopathy. Vasculopathy is another dangerous risk factor and hallmark of chronic allograft rejection triggered by multifactorial immunologic events, characterized by endothelial injury and dysfunction, myointimal hyperplasia and extracellular matrix synthesis ( 55 , 56 ). Transplant vasculopathy inevitably occurs in ~90% of allografts, developing severe intimal hyperplastic lesions that eventually result in luminal flow restriction and graft failure during long-term follow-up ( 57 ).…”