[Background] Preformed and newly formed alloantibody post transplantation (TX) can significantly deteriorate graft survival. Patterns of humoral rejection in sensitized patients varies significantly due to differences in sensitization levels, quality or immunosuppression. Using a preclinical model of sensitized kidney TX in non-human primates (NHP), we describe distinct patterns of antibody-mediated injury in sensitized recipients.

[Methods] Seven fully mismatched rhesus macaques were sensitized with skin TX. Immunologic responses were confirmed using T- and B-cell flow cytometry crossmatch (FXM). After stabilization animals underwent native nephrectomy and kidney TX from their skin donor. Immunosuppression included induction with anti-rhesus CD4 and CD8 antibodies, maintenance therapy using Tacrolimus and Mycophenolate and tapered steroids. Assessment comprised laboratory testing, FXM, urine output and clinical monitoring. After sacrifice kidney grafts were submitted to pathology for H&E, PAS, Trichrome and C4d staining.

[Results] T-cells were effectively reduced, mean CD4 cells by 93.5% and CD8 cells by 100% (p=0.0042) in the first week after TX; this was sustained throughout post-transplant survival. All animals had to be sacrificed due to clinical state in association with kidney malfunction. One monkey suffered failure within 24 hours and 3 grafts stopped producing urine within 8 days. The remaining animals survived for 27, 43 and 44 days. These two different phenotypes were reflected in histologic findings. 7/8 grafts were rejected and had features of antibody injury such as glomerulitis, pertibular capillaritis and at least focal C4d staining. The early rejectors (n=3) tended to have glomerular thrombotic microangiopathy but little interstitial inflammation, no features of cellular rejection. 2 cases of later rejectors (n=3) showed no fibrin thrombi but considerable interstitial inflammation and discrete suspicion for beginning cellular involvement. The last case showed mixed rejection that correlated retrospectively with suboptimal T-cell depletion.

[Conclusion] Distinct histologic features in kidney allografts are still hard to correlate with definitive pathophysiology. Different patterns in sensitized NHP can help to distinguish sources of injury, these mechanisms may warrant different prognostic and therapeutic implications in clinical practice.

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