A Model of Acute Antibody-Mediated Renal Allograft Rejection in the Sensitized Rata.

Abstract

Antibody-mediated rejection in transplant recipients with preexisting donor-specific antibodies is a challenging clinical situation. However, we lack suitable animal models to study this scenario. The aim of this study was to develop an animal model of acute antibody-mediated rejection of renal allografts in sensitized recipients. We used major histocompatibility complex class I and II incompatible rat strains (Dark Agouti RT1av1 and Lewis RT1l), which develop aggressive rejection. Recipient Lewis rats were immunized with donor strain spleen cells 5 days before surgery to induce donor-specific antibodies. Rats underwent bilateral nephrectomy and orthotopic transplant of the donor kidney. To minimize T-cell-mediated rejection while allowing the development of donor-specific antibodies, recipient animals were given tacrolimus starting the day before surgery. Hyperacute rejection was not seen, but acute graft dysfunction was evident on day 1 with a rapid deterioration of graft function by day 3. Histologic damage featured glomerulopathy, capillaritis, capillary thrombosis, and acute tubular injury. Recipients exhibited high serum levels of donor-specific antibodies and deposition of immunoglobulin G and C4d on graft endothelium. Immunostaining showed substantial endothelial damage, fibrin deposition in glomerular and peritubular capillaries, and infiltrates of macrophages, neutrophils, and natural killer cells. T-cell activation was efficiently suppressed by tacrolimus. We have developed a clinically relevant model of acute antibody-mediated rejection in recipients with preexisting donor-specific antibodies, which is suitable for testing novel therapies.