Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase

Abstract

In organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA‐mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon‐γ (IFN‐γ)‐induced HLA class II DR (HLA‐DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%; P < 0.01) and fluvastatin (FLU, 33.8% ± 0.6%; P < 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA‐DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA‐DR. Imaging analysis revealed that HLA‐DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%, P < 0.01; cell surface: 80.9% ± 4.0%, P < 0.01) and FLU (cytosol: 19.0% ± 3.4%, P < 0.01; cell surface: 48.3% ± 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed IFN‐γ‐induced HLA‐DR expression at the transcriptional and post‐translational level, respectively, suggesting a potential approach for alleviating DSA‐related issues in organ transplantation.

BCL6 regulates the endothelial pro-immunogenic phenotype relevant to organ transplant rejection

“…Standard immunosuppression (CSA, TAC) did not affect IFNγ-induced HLA-DR expression on endothelium 85 . However, our results demonstrate that overexpression or pharmacological targeting of BCL6 effectively suppressed HLA-DR and HLA-DP expression, with had variable effect on HLA-DQ.…”

The case for the therapeutic use of mechanistic/mammalian target of rapamycin (mTOR) inhibitors in xenotransplantation

“…33 In human vein endothelial cells, mTOR inhibition reduces IFN-γ-induced human leukocyte antigen (HLA)-class II expression. 34 These results suggest that the effects of mTOR inhibition in suppressing the immune response and inflammation are exerted not only on the recipient's immune system, but also on the donor graft. mTOR-Is have anti-inflammatory effects and subsequent suppression of the immune response.…”

“…In addition, mTOR‐Is suppress the mTOR‐signal transducer and activator of transcription (STAT) 3 pathway and reduce protein and mRNA levels of IFN‐γ and IL‐17 in splenocytes 33 . In human vein endothelial cells, mTOR inhibition reduces IFN‐γ‐induced human leukocyte antigen (HLA)‐class II expression 34 …”

Effect of Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors on the Course of COVID-19 in Kidney Transplant Recipients

“…Bourboulis et al evaluated immune responses of COVID-19 patients (n=54) with macrophage activation syndrome and found that CD4+ T lymphocytes, CD19+ B lymphocytes, and NK cells, and their human leucocyte antigen (HLA)-DR expression were significantly decreased [ 29 ]. In another study, everolimus reduced the amount of interferon gamma (IFN-gamma)-induced HLA-DR in endothelial cells [ 30 ]. In contrast, tacrolimus affects basal or IFN-gamma-induced HLA-DR in monocytic cell lines [ 31 ].…”