Preventative effect of TSPO ligands on mixed antibody-mediated rejection through a Mitochondria-mediated metabolic disorder.

ABSTRACT:

Background

Immune-mediated rejection was the major cause of graft dysfunction. Although the advances in immunosuppressive agents have markedly reduced the incidence of T-cell-mediated rejection after transplantation. However, the incidence of antibody-mediated rejection (AMR) remains high. Donor-specific antibodies (DSAs) were considered the major mediators of allograft loss. Previously, we showed that treatment with 18-kDa translocator protein (TSPO) ligands inhibited the differentiation and effector functions of T cells and reduced the rejection observed after allogeneic skin transplantation in mice. This study we further investigate the effect of TSPO ligands on B cells and DSAs production in the recipients of mixed-AMR model.

Methods

In vitro, we explored the effect of treatment with TSPO ligands on the activation, proliferation, and antibody production of B cells. Further, we established a heart-transplantation mixed-AMR model in rats. This model was treated with the TSPO ligands, FGIN1-27 or Ro5-4864, to investigate the role of ligands in preventing transplant rejection and DSAs production in vivo. As TSPO was the mitochondrial membrane transporters, we then investigated the TSPO ligands effect on mitochondrial-related metabolic ability of B cells as well as expression of downstream proteins.

Results

In vitro studies, treatment with TSPO ligands inhibited the differentiation of B cells into CD138⁺CD27⁺ plasma cells; reduced antibodies, IgG and IgM, secretion of B cells; and suppressed the B cell activation and proliferation. In the mixed-AMR rat model, treatment with FGIN1-27 or Ro5-4864 attenuated DSA-mediated cardiac-allograft injury, prolonged graft survival, and reduced the numbers of B cells, including IgG⁺ secreting B cells, T cells and macrophages infiltrating in grafts. For the further mechanism exploration, treatment with TSPO ligands inhibited the metabolic ability of B cells by downregulating expression of pyruvate dehydrogenase kinase 1 and proteins in complexes I, II, and IV of the electron transport chain.

Conclusions

We clarified the mechanism of action of TSPO ligands on B-cell functions and provided new ideas and drug targets for the clinical treatment of postoperative AMR.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC10152746 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature