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Does human leukocyte antigens sensitization matter for xenotransplantation?

Byrne, GW; (2018) Does human leukocyte antigens sensitization matter for xenotransplantation? Xenotransplantation , 25 (3) , Article e12411. 10.1111/xen.12411. Green open access

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Abstract

The major histocompatibility complex class I and class II human leukocyte antigens (HLA) play a central role in adaptive immunity but are also the dominant polymorphic proteins targeted in allograft rejection. Sensitized patients with high levels of panel‐reactive anti‐HLA antibody (PRA) are at risk of early allograft injury, rejection, reduced allograft survival and often experience prolonged waiting times prior to transplantation. Xenotransplantation, using genetically modified porcine organs, offers a unique source of donor organs for these highly sensitized patients if the anti‐HLA antibody, which places the allograft at risk, does not also enhance anti‐pig antibody reactivity responsible for xenograft rejection. Recent improvements in xenotransplantation efficacy have occurred due to improved immune suppression, identification of additional xenogeneic glycans, and continued improvements in donor pig genetic modification. Genetically engineered pig cells, devoid of the known xenogeneic glycans, minimize human antibody reactivity in 90% of human serum samples. For waitlisted patients, early comparisons of patient PRA and anti‐pig antibody reactivity found no correlation suggesting that patients with high PRA levels were not at increased risk of xenograft rejection. Subsequent studies have found that some, but not all, highly sensitized patients express anti‐HLA class I antibody which cross‐reacts with swine leukocyte antigen (SLA) class I proteins. Recent detailed antigen‐specific analysis suggests that porcine‐specific anti‐SLA antibody from sensitized patients binds cross‐reactive groups present in a limited subset of HLA antigens. This suggests that using modern genetic methods, a program to eliminate specific SLA alleles through donor genetic engineering or stringent donor selection is possible to minimize recipient antibody reactivity even for highly sensitized individuals.

Type: Article
Title: Does human leukocyte antigens sensitization matter for xenotransplantation?
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/xen.12411
Publisher version: https://doi.org/10.1111/xen.12411
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: anti‐HLA, non‐Gal antibody, panel‐reactive antibody, xenoreactive antibody, xenotransplantation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: https://discovery.ucl.ac.uk/id/eprint/10049330
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