Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection

Background and aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4⁺ T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and directing the differentiation of CD4⁺ T cells toward immunosuppression are keys to inhibiting ACR. We propose that oxymatrine (OMT), a quinolizidine alkaloid, either alone or in combination with rapamycin (RAPA), attenuates ACR by inhibiting the mTOR-HIF-1α pathway.

Methods: Graft damage was assessed using haematoxylin and eosin staining. Intragraft CD11c⁺ and CD4⁺ cell infiltrations were detected using immunohistochemical staining. The proportions of mature DCs, T helper (Th) 1, Th17, and Treg cells in the spleen; donor-specific antibody (DSA) secretion in the serum; mTOR-HIF-1α expression in the grafts; and CD4⁺ cells and bone marrow-derived DCs (BMDCs) were evaluated using flow cytometry.

Results: OMT, either alone or in combination with RAPA, significantly alleviated pathological damage; decreased CD4⁺ and CD11c⁺ cell infiltration in cardiac allografts; reduced the proportion of mature DCs, Th1 and Th17 cells; increased the proportion of Tregs in recipient spleens; downregulated DSA production; and inhibited mTOR and HIF-1α expression in the grafts. OMT suppresses mTOR and HIF-1α expression in BMDCs and CD4⁺ T cells in vitro.

Conclusions: Our study suggests that OMT-based therapy can significantly attenuate acute cardiac allograft rejection by inhibiting DC maturation and CD4⁺ T cell responses. This process may be related to the inhibition of the mTOR-HIF-1α signaling pathway by OMT.