Background: Chronic renal allograft rejection (CR) is the leading cause of late renal transplant failure. The histological lesions of CR may comprise glomerular basement membrane (GBM) duplications and mesangiolysis. Its pathogenesis is not yet completely understood, although lately humoral responses have been suggested to be important. Recently, we identified antibody responses directed against GBM antigens in the Fischer (F344) to Lewis (LEW) renal transplantation model. Immunofluorescent studies in this model also suggested deposition of antibodies on mesangial cells. Therefore, we hypothesized that antibodies were not only directed at GBM antigens but also to mesangial cell antigens.
Methods: F344 to LEW renal transplantations were performed and sera were collected. Pre- and post-transplantation sera were tested for antibody binding to donor rat mesangial cells (RMCs) cultured from F344 kidneys. Anti-mesangial cell antibodies were compared with anti-GBM antibodies measured in the same sera.
Results: Post-transplant sera of F344 to LEW renal transplantations, but not LEW to F344, bound to F344 RMC in a dose-dependent manner. Whereas antibodies reactive with RMCs were not present before transplantation, all rats with CR developed antibodies. The antibodies were predominantly of the IgG1 isotype. Antibody binding to RMCs correlated with binding to F344 GBM. Pre-incubation with RMCs partially inhibited GBM binding, and RMC binding was inhibited by GBM. Antibody binding to RMCs did not result in complement activation or cell lysis.
Conclusion: LEW recipients of F344 grafts produce antibodies reactive with F344 RMCs. The antigens involved are similar to or at least share antigenic epitopes with antigens recognized in the GBM.