L6H21 prolonged rats survival after limb allotransplantation by inhibiting acute rejection

F.-Z. Yu, X. Wen, W.-L. Ding, J.-Y. Zhu, S.-H. Du, Q.-F. Shen, X. Ni, J. Wang

Department of Hand Surgery and Peripheral-neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. Jianwang0516@126.com

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• Pharmacology

OBJECTIVE: Preventing and reducing allograft rejection play a far more important role in limb allotransplantation. We previously found L6H21 could inhibit LPS-induced (lipopolysaccharide LPS) overexpression inflammatory factors in macrophages and specifically targets to MD-2 (myeloid differential protein-2 MD-2) required for TLR4 (Toll-like receptor 4 TLR4) activation and represented an important therapeutic target in inflammatory disorders. Therefore, we evaluated the effect and explored the mechanism of L6H21 in rats’ limb allograft model.

MATERIALS AND METHODS: The efficacy of L6H21 was evaluated in limb allograft rats and cyclosporine (CY-A) was used as a positive control agent. T-Lymphocyte in blood was analyzed and dendritic cells (DCs) separated from spleens using flow cytometry. ELISA was used to measure serum cytokine levels. Analysis of protein expressions was performed using Western blotting.

RESULTS: L6H21 reduced the risk of acute rejection and prolonged survival of limb allograft rats. At 3 d and 5 d post-transplant, the ratio of CD4+/CD8+ was decreased in L6H21 group. L6H21 suppressed the content of IL-1α at 7d, IL-5 and IL-10 at both 3 d and 7 d after transplantation. L6H21 decreased the protein expressions of IRF3, p-IRF3, P38, p-P38 and p-IκBα while increased IκBα expression and decreased the ratio of p-IRF3/ IRF3, p-P38/ P38, p-IκBα/IκBα correspondingly.

CONCLUSIONS: L6H21 could reduce the risk of acute rejection and prolong the survival of limb allograft rats through inhibiting the ratio of CD4+/CD8+ in blood and serum cytokine levels and suppressing protein expressions of IRF3, p-IRF3, P38, p-P38 and p-IκBα in DCs. So, it may serve as a potential candidate for the treatment of allograft rejection.

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