Long-Term Survival of Pig-to-Rhesus Macaque Renal Xenografts is Dependent on CD4 T cell Depletion.

The shortage of available organs remains the greatest barrier to expanding access to transplantation. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplantation has generally been limited to <100 days. We found that pre-transplant selection of recipients with low titers of anti-pig antibodies significantly improved survival in a pig to rhesus macaque kidney transplant model (6 days vs MST 235 days). Immunosuppression included transient pan-T cell depletion and an anti-CD154-based maintenance regimen. Selective depletion of CD4+ T cells but not CD8+ T cells resulted in long-term survival (MST >400 days vs 6 days). These studies suggested that CD4+ T cells may have a more prominent role in xenograft rejection compared to CD8+ T cells. While animals that received selective depletion of CD8+ T cells showed signs of early cellular rejection (marked CD4+ infiltrates), animals receiving selective CD4+ depletion exhibited normal biopsies until late where signs of chronic antibody rejection were present. In-vitro studies suggested that rhesus CD4+ T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pre-transplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival. This article is protected by copyright. All rights reserved.