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.
Highlights
Organ transplantation is an ideal and final solution for patients suffering end-stage organ diseases [1]
Previous studies have reported inflammation as a primary mechanism of transplant vasculopathy (TV) development [6], the formation of TV needs the involvement of the interferon (IFN)-γ axis, as TV do not Triptolide Attenuates Transplant Vasculopathy occur in settings of congenital absence or neutralizing antibody blockade of IFN-γ [7, 8]
We established an allogeneic aortic graft model, and the recipients were treated with or without triptolide for 4 weeks; subsequently, allografts were harvested and tissue sections were stained with hematoxylin and eosin to visualize TV lesions
Summary
Organ transplantation is an ideal and final solution for patients suffering end-stage organ diseases [1]. Approximately 90% of allografts are likely to develop transplant vasculopathy (TV) during long-term follow-up [2]. Previous studies have reported inflammation as a primary mechanism of TV development [6], the formation of TV needs the involvement of the interferon (IFN)-γ axis, as TV do not Triptolide Attenuates Transplant Vasculopathy occur in settings of congenital absence or neutralizing antibody blockade of IFN-γ [7, 8]. Some reports demonstrate that antibodies are independent risk factors for long-term survival of recipients, and can cause or contribute to TV [10, 11]. Vascular smooth muscle cell (VSMC) migration and proliferation are key events involved in TV development [12, 13]. Given the numerous pathogenic factors associated with TV, there is no effective therapeutic strategy capable of simultaneously regulating its multiple pathogenic pathways
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