Bortezomib and sirolimus inhibit the chronic active antibody-mediated rejection in experimental renal transplantation in the rat

Abstract

To date, no effective immunosuppressive standard for the prevention or treatment of alloantibody production in acute and chronic rejection of renal transplants has been established. Alloantibody formation has been recognized in the well-established rat model of Fischer to Lewis renal transplantation. We used this renal allotransplantation model to test the effectiveness of sirolimus (SRL), bortezomib (BZ) or their combination in an already established humoral rejection situation. After 3weeks, transplanted rats were treated either with placebo (P), SRL, BZ or combination of SRL and BZ. Rats were monitored for donor-specific alloantibodies as well as humoral responses in the spleen and bone marrow, renal function and histological changes in the graft. In all three treatment arms, glomerular, tubulointerstitial and vascular changes of chronic antibody-mediated rejection were ameliorated compared to the P group. Production of alloantibodies against components of glomerular basement membrane was reduced in all three treatment arms. The humoral response was strongly reduced, as shown by decreased numbers of IgG-secreting cells, plasma cells and partially B cells in all treatment groups with a trend of SRL/BZ combination being most effective. Infiltration of the graft with inflammatory cells like cytotoxic T cells, T helper cells, B cells and macrophages was efficiently blocked by BZ and the SRL/BZ combination and, except for B cells, by SRL. BZ and SRL represent promising drugs with anti-humoral activity in the situation of an already established chronic humoral or mixed alloimmune response after renal transplantation.