ABO-Incompatible Transplantation Might Have the Potential to Reduce Anti-HLA Class II DR-Mediated CAMR.

Abstract

[Purpose] ABO-incompatible renal transplantation is now safely conducted. Attention has been directed towards long-term graft outcome, particularly anti-HLA class II antibody-induced chronic antibody mediated rejection (CAMR). Although favorable graft survival in ABO-incompatible transplantation has been recently reported, the preventive effect of B-cell targeted therapy such as rituximab on CAMR remains controversial, particularly in light of long-term effect. We have suggested the possibility of accommodation caused by anti-A/B antibody binding. The purpose of this study was to analyze the protective effect of anti-A/B antibody ligation on endothelial cells against anti-HLA DR antibody-mediated injury. [Method] Human EA.hy926 endothelial cells expression A/B antigen were treated with IFNγ for 2 days to express HLA-DR on cell surface. Complement regulatory genes and HO-1/Ferritin H mRNA expression were measured by flow cytometry and quantitative RT-PCR, respectively. AKT and ERK activity were defined by Western blotting. [Result] Expression of HLA-DR on EA.hy926 endothelial cells was elicited by IFNγ treatment. HLA class I expression was also increased about 4-5 fold. Anti-HLA class II DR IgG antibody purified from patient sera decreased CD59 expression. When treated with IFNγ, anti-HLA class I and DR antibody binding to endothelial cells did not show any cytoprotective effect against complement-mediated cytotoxicity (CDC) nor activation of AKT pathway, whereas pre-incubation with anti-A antibody was proven to acquire resistance to CDC. [Discussion] The presence (or ligation) of anti-A/B antibody could reduce anti-HLA antibody-mediated CDC to IFNγ-activated (A/B-expressing) endothelial cells, which implies “long-term” beneficial effect of anti-A/B antibody binding on CAMR It is speculated that sustained anti-A/ B antibody ligation might exhibit cytoprotective effects by modifying CD59 expression and AKT pathway.