Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study.
Deep multimodal phenotyping of two genetically engineered pig kidneys transplanted into decedent humans found early signs of antibody-mediated rejection despite favorable short-term outcomes, pointing to the humoral immune response as a key therapeutic target for xenotransplantation.
Background
Cross-species immunological incompatibilities have long hampered pig-to-human kidney xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. Little was known about the human immune response after transplantation of pig kidneys, and the authors aimed to characterize the early immune reaction using a multimodal deep phenotyping approach.
Study design
The team performed complete phenotyping of two pig kidney xenografts transplanted into decedent human recipients, combining morphological evaluation, immunophenotyping (IgM, IgG, C4d, CD68, CD15, NKp46, CD3, CD20, and von Willebrand factor), gene expression profiling, and whole-transcriptome digital spatial profiling with cell deconvolution. Controls included xenografts before implantation, wild-type pig kidney autografts, and non-transplanted wild-type pig kidneys with and without ischaemia-reperfusion.
Key findings
The xenografts showed early signs of antibody-mediated rejection, characterized by microvascular inflammation with immune deposits, endothelial cell activation, and positive xenoreactive crossmatches. Capillary inflammation was composed mainly of intravascular CD68 and CD15 innate immune cells along with NKp46 cells, and gene expression linked to a humoral response was increased. Spatial profiling localized antibody-mediated injury predominantly to the glomeruli, with enrichment of monocyte, macrophage, neutrophil, and natural killer cell transcripts not seen in control kidneys.
Clinical implications
Despite favorable short-term outcomes and the absence of hyperacute injury, the findings suggest antibody-mediated rejection may already be occurring in pig-to-human kidney xenografts. The authors propose that therapies targeting the humoral arm of rejection could improve xenotransplantation results. The analysis is based on only two xenografts in decedent recipients, so conclusions about longer-term immune behavior remain preliminary.
Category
Transplant
Source
Lancet
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