Triptolide Attenuates Transplant Vasculopathy Through Multiple Pathways

Abstract

Background: Transplant vasculopathy (TV) is a hallmark of chronic allograft rejection the primary cause of allograft loss after organ transplantation. Because multiple mechanisms are involved in TV pathogenesis, effective therapy for it remains deficiency. This study aimed to identify the role of triptolide, which has a wide spectrum of immuno-suppressive activities, in inhibiting TV development. Methods: Mice aortic transplant models were constructed and divided into triptolide-treatment and control group. The pathological changes of allograft were determined by hematoxylin and eosin, the expression of intragraft pro-inflammatory and pro-fibrogenic factors were detected by immunohistochemistry, qRT-PCR and flow cytometry. Subsequently, transwell assay was used to determine the inhibitory effect of triptolide on vascular smooth muscle cell (VSMC) migration in vitro. Findings: Triptolide significantly alleviated intima thickening of allograft by inhibiting multiple pathways. Triptolide inhibited IFN-γ and IFN-γ-inducing factor expression accompanied by significant attenuation of circulating and spleen IFN-γ-producing T lymphocytes. Additionally, triptolide markedly decreased intragraft CD3+, CD4+, and CD8+ T lymphocytes and CD68+ macrophages numbers, as well mRNA levels of pro-inflammatory and pro-fibrogenic factors. Moreover, triptolide significantly decreased the proportion of B lymphocytes and plasma cells in recipient, and notably reduced the level of circulating donor-specific antibodies. Furthermore, we demonstrated for the first time that triptolide significantly inhibits migration of VSMC without affecting their viability and apoptosis in vitro. Interpretation: These results emphasize the efficacy of triptolide in inhibiting TV development and provide a basis for developing new treatments to prevent chronic allograft rejection and improve the long-term viability of transplant recipients. Funding Statement: This work was funded by the National Natural Science Foundation of China (No. 81970650, 81770753, 81800663); National Key RD the Natural Science Foundation of Guangdong Province (No. 2019A1515011942). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Animals were housed in a specific pathogen-free facility at Sun Yat-sen University (Guangdong, China), and all animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication No. 80-23, revised 1996) and according to the Sun Yat-sen University Institutional Ethical Guidelines for animal experiments.