Swine Xenografts Share Few Predicted Indirectly Recognisable SLA‐Derived Epitopes With HLA‐Derived Epitopes From Human Kidney Grafts

TL;DR

This study finds that pig kidneys for human transplants have few shared T cell epitopes with human kidneys, suggesting a lower risk of immune rejection in repeat transplants.

Contribution

The study computationally evaluates shared T cell epitopes between human and swine grafts, revealing low cross-species memory T cell activation risk.

Findings

HLA and SLA proteins show structural similarities but distinct linear sequences and peptidomes.

Swine xenografts share a median of 1 T cell epitope with human kidneys, compared to 17 between two human kidneys.

Xenotransplantation may offer grafts for HLA-sensitized recipients with low memory T cell activation risk.

Abstract

Swine‐derived kidneys are a promising alternative organ source for transplantation, but compatibility in the major histocompatibility complex remains an immunological barrier. Furthermore, in repeat transplantations, CD4+ memory T cells can lead to a more rapid immune response against repeated exposure to the same antigens. Several studies have shown that HLA and SLA proteins share overlapping B cell epitopes due to structural or electrostatic similarities, but the role of overlapping T cell epitopes has not been fully explored. This study aims to computationally analyse the potential risk of memory T cell activation in subsequent human‐after‐swine and swine‐after‐human transplantation by evaluating shared T cell epitopes between the two graft sources. We show that while HLA and SLA demonstrate striking structural similarities, their linear protein sequences are very distinct, which translates to disparate HLA‐ and SLA‐derived peptidomes and T cell epitopes. By applying the PIRCHE‐II Tmem analysis to a simulated panel of recipients receiving repeat transplantations from a human kidney and from a swine xenograft, we observed a median of 1 shared T cell epitope in the cross‐species context, compared to a median of 17 shared between two human‐derived kidneys. This suggests that a swine xenograft exposes a low risk of T cell memory against a later human donor, and that xenotransplantation may provide an opportunity to receive a graft for highly HLA‐sensitised recipients.

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