The Role of SLAs in Xenotransplantation

Abstract

Advances in genetic engineering, particularly CRISPR/Cas9, have resulted in the development of a triple glycan-knockout (TKO) pig. There is minimal human antipig antibody binding to TKO pig cells. The TKO background has decreased antibody binding to a sufficiently low level that any additional xenoantigens expressed on the cells can now be more easily detected. One of these xenoantigens is the swine major histocompatibility complex, termed swine leukocyte antigens (SLA). SLA are the homolog to HLAs, a protein complex expressed on human tissue capable of stimulating the development of new antibodies in allotransplantation. These antibodies can result in graft failure through hyperacute, acute, or chronic rejection. Our knowledge of SLA, particularly in the last 5 years, has grown considerably. The presence, cause, and methods to detect anti-SLA antibodies will need to be carefully considered for the first clinical trial of xenotransplantation. The focus of this review is to summarize the role of SLA in xenotransplantation and consider whether it will prove to be a major barrier. Techniques are now available to mutate target SLA amino acids to ensure that cross-reactive anti-HLA antibodies no longer bind to SLA on the cells of the organ-source pigs. While deletion of SLA expression is possible, it would render the pig at risk for infectious complications. The ideal organ-source pig for HLA highly sensitized recipients may therefore be 1 with site-specific mutations to eliminate cross-reactive binding.

Pig kidney xenotransplantation: Progress toward clinical trials

“…Many patients with antibodies to human leukocyte antigens (HLA) do not appear to be at any increased risk of rejection of a pig kidney graft 35‐37 . However, in some patients there may be cross‐reactivity between anti‐HLA antibodies and SLA 38‐40 . We therefore suggest that, to avoid any risk of cross‐reactivity, only patients with no anti‐HLA antibodies should be considered for the initial clinical trials.…”

“…[35][36][37] However, in some patients there may be cross-reactivity between anti-HLA antibodies and SLA. [38][39][40] We therefore suggest that, to avoid any risk of cross-reactivity, only patients with no anti-HLA antibodies should be considered for the initial clinical trials.…”

Comparative analysis of swine leukocyte antigen gene diversity in European farmed pigs

“… 2020 ; Ladowski et al . 2021 ). To understand and control SLA complexity, mainly miniature swine models are used to establish SLA‐inbred/‐defined pig lines (reviewed in Hammer et al .…”

Upfront use of eculizumab to treat early acute antibody‐mediated rejection after kidney allotransplantation and relevance for xenotransplantation

“…In xenotransplantation, the key role of complement in mediating tissue injury, for example, in pig to primate hyperacute or acute humoral rejection (acute AMR), has been known for many years, and various approaches to help protecting recipients against the complement cascade have been progressively developed to improve results 1 . Similarly, early acute and active AMR after kidney allotransplantation in humans is a rare but potentially dramatic complication, if not rapidly diagnosed and adequately treated 2 .…”

“…Similar to the early acute humoral rejections occurring in discordant xenotransplantation (eg, due to anti‐pig antibodies in monkey recipients), early acute antibody‐mediated rejection (AMR) in highly sensitized recipients after kidney allotransplantation currently remains an important immunological and therapeutic challenge 1,2 . Complement activation and its associated tissue injury plays an important pathogenic role in most early (less than 30 days post‐transplant) acute AMR episodes, and therefore, complement inhibition may be beneficial in that setting 2 .…”