The development of accelerated antibody-mediated rejection (ABMR) is associated with early allograft dysfunction and premature graft loss. In animals, pre-sensitization is usually required in order to progress to antibody-mediated injury of the graft. In this study, we developed a model of de-novo ABMR after renal transplantation in rhesus macaques receiving organs from brain-dead (BD) donors. BD was induced by inflation of a subdural balloon catheter and donors were monitored for 20 hours followed by a 40-hour cold ischemia period. Kidneys were transplanted into fully mismatched, ABO-compatible recipients and native kidneys removed. All recipients had a negative donor-specific antibody (DSA) at baseline for Class I and II antigens by FACS and Luminex technology. Recipients did not receive induction therapy and were maintained on a tacrolimus, mycophenolate and prednisone immunosuppressive regimen. Animals were followed for a 90-day period and underwent interval biopsies at post-transplant days 15, 30, 60 and 90. Two recipients developed DGF (28.6%), three progressed to ABMR (42.8%) and two animals survived for 90 days (28.6%) with no evidence of rejection. Animals developing ABMR showed a progressive decline in renal function and shorter mean survival compared to non-rejecting recipients (34.3 ± 4.0 vs. 90 days, respectively, p=0.05). Kidney biopsies were evaluated using the Banff 2013 classification and recipients progressing to ABMR showed sustained DSA development post-transplantation which correlated to deteriorating renal function and biopsy changes. At necropsy, histopathological findings were consistent with acute active and chronic active ABMR in the kidney as evidenced by strong C4d staining and microvascular injury characterized by peritubular capillaritis and glomerulitis in all rejecting recipients. Moreover, FACS analysis revealed a higher proportion of class-switched memory B-cells (CD20⁺, CD27⁺, IgD^low) in mesenteric and inguinal lymph nodes from ABMR recipients compared to negative subjects. In summary, we have developed a model of de-novo accelerated ABMR in rhesus macaques undergoing transplantation with kidneys from brain-dead donors. This highly translatable model provides a platform to study the mechanisms of de-novo DSA formation and for the development and testing of therapeutic strategies to prevent progression to ABMR and graft failure.

CITATION INFORMATION: Danobeitia J, Chlebeck P, Torrealba J, Zens T, Zitur L, D'Alessandro A, Fernandez L. Accelerated De-Novo Donor-Specific Antibody-Mediated Rejection in a Non-Human Primate Model of Renal Transplantation. Am J Transplant. 2017;17 (suppl 3).

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