*Purpose: After kidney transplantation, Antibody Mediated Rejection (ABMR) is the main factor affecting the long-term survival of kidney transplantation. Previous studies have confirmed that macrophage polarization is significantly activated in ABMR and can promote endothelial cell injury mediated by Donor Specific Antibody (DSA). Iguratimod (IGT) can slow down the occurrence of ABMR in vivo, which may be related to the inhibition of polarization of M1 macrophages. The purpose of this study was to explore the effect of M1 macrophage polarization on ABMR after renal transplantation and the mechanism of the effect of IGT.

*Methods: We pre-sensitized recipients Balb/c mice with donors C57BL/6 mice by skin transplantation and constructed ABMR model by abdominal ectopic kidney transplantation from donors to skin pre-sensitized recipients. Based on ABMR models, we intervened with IGT to explore the effect of IGT on ABMR. Flow cytometry was used to detect the changes of DSA titers in peripheral blood, monocytes/macrophages in peripheral blood and monocytes/macrophages infiltrated from transplanted kidney. Immune microsphere method was used to detect the expression of cytokines in peripheral blood of mice. In addition, we extracted and cultured Bone Marrow Derived Macrophage (BMDM). Based on it, BMDMs were stimulated to polarize M1 macrophages and were interfered with IGT to explore the effect of IGT in vivo. RNA sequencing was used to detect the mechanism during BMDM polarization.

*Results: IGT can significantly protect graft renal function and prolong the survival time of mice in ABMR group. The pathological results showed that IGT could significantly reduce the incidence of peritubular capillary vasculitis and arteriolitis in ABMR mice, decrease the expression of C4d in transplanted kidneys, and alleviate graft kidney injury. Flow cytometry results showed that IGT could reduce the titer of DSA in peripheral blood of mice, inhibit the activation of monocytes/macrophages, and decrease the number of M1 macrophages infiltrated in the transplanted kidney. Transcriptomic sequencing results suggested that IGT might inhibit the activation of Nuclear Factor-κB (NF-κB) inflammatory pathway by blocking the activation of jagged1-Notch4 signaling pathway of macrophages, which could prevent polarization of M1 macrophages and alleviate inflammatory response.

*Conclusions: Polarization of M1 macrophages may aggravate ABMR after renal transplantation by promoting DSA-mediated endothelial cell injury. IGT may inhibit the activation of NF-κB inflammatory pathway by inhibiting the activation of Jagged1-Notch4 signaling pathway, and then prevent the polarization of M1 macrophages.

« Back to 2022 American Transplant Congress