Abstract
ABSTRACT
Introduction
“Delayed” antibody‐mediated xenograft rejection is one of the most important obstacles to clinical application of pig organ xenografts. The aim of this study was to assess the impact of a structured desensitization regimen including proteasome inhibition and next‐generation costimulation blockade on xenoreactive antibodies.
Methods
Rhesus macaques with moderate‐high pre‐treatment xenoreactive antibody titers (N = 2) were selected. Recipients received twice‐weekly carfilzomib (20 mg/m2), anti‐CD154 (20 mg/kg) every other week, and CD4 and CD20 lymphocyte cell depletion. Bone marrow was acquired to assess plasma cell depletion in response to proteasome inhibition. A flow cytometry‐based xenoreactive crossmatch assay was performed to assess levels of circulating xenoreactive antibodies.
Results
The desensitization regimen resulted in a >50% depletion of CD38+CD27+ bone marrow plasma cells; these changes were progressive over the duration of the desensitization treatment period. The desensitization strategy and plasma cell depletion resulted in a progressive reduction in anti‐pig IgG antibodies. Following xenotransplantation, both desensitized recipients demonstrated superior graft survival to a highly xenoreactive recipient (MST 30 days vs. 6 days), but neither desensitized recipient experienced prolonged graft survival.
Conclusions
A structured desensitization regimen including proteasome inhibition and costimulation blockade results in plasma cell depletion and resultant reduction in circulating xenoreactive anti‐pig IgG antibodies, with a modest improvement in xenograft survival. This desensitization regimen has promise for pig‐to‐NHP xenotransplant models.