Chronic Antibody Mediated Rejection of Renal Allografts: Pathological, Serological and Immunologic Features in Nonhuman Primates

The pathogenesis of late renal allograft loss is heterogeneous and difficult to diagnose. We have analyzed renal allografts in nonhuman primates to determine the relationship between alloantibodies and the graft pathology of late graft loss. Seventeen Cynomolgus monkeys were chosen from among those on several protocols for renal allotransplantation with mixed chimerism induction so that animals with and without alloantibodies were included. All animals received transient CD154 blockade and short-term cyclosporine treatment until day 28. Serial blood samples were tested for alloantibodies. Protocol biopsies and autopsy kidneys were scored for pathology and C4d deposition. Group 1, defined by complete lack of C4d deposition (24 tissue samples; 8 recipients), had no detectable alloantibodies (33 serum samples; 1-7 samples per recipient) and no evidence of chronic rejection. Three survived greater than 2 years with normal function and histology. Group 2, defined as having C4d deposition in peritubular capillaries, all made alloantibodies (100%), and most grafts later showed chronic allograft glomerulopathy (89%), and/or arteriopathy (89%). All grafts in Group 2 failed (3-27 months). Pathologic lesions of typical of chronic rejection in humans develop in monkeys, correlate with antecedent alloantibodies/C4d deposition and predict chronic rejection rather than durable accommodation.