Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study

Porcine genome engineering has advanced pig-to-human xenotransplantation, yet little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterize the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach.

To this end, we phenotyped two pig kidney xenografts transplanted to decedent humans. We used a multimodal strategy combining morphological evaluation, immunophenotyping, gene expression profiling (Nanostring nCounter), and spatial profiling (Nanostring GeoMx), with controls including pre-implantation xenografts, wild-type pig kidney autografts, and non-transplanted pig kidneys. 

Xenograft data revealed early signs of antibody-mediated rejection, marked by microvascular inflammation, endothelial cell activation, and positive xenoreactive crossmatches. Capillary inflammation consisted mainly of CD68+, CD15+, and NKp46+ cells. Both xenografts showed increased expression of genes biologically related to a humoral response, including monocyte and macrophage activation, natural killer cell burden, endothelial activation, complement activation, and T-cell development. Whole-transcriptome digital spatial profiling showed that antibody-mediated injury was mainly located in the glomeruli of the xenografts, with significant enrichment of transcripts associated with monocytes, macrophages, neutrophils, and natural killer cells. This phenotype was absent in controls.

Despite initial success and lack of hyperacute injuries, our findings suggest antibody-mediated rejection in pig-to-human kidney xenografts. Targeting the humoral arm of rejection could enhance xenotransplantation outcomes.