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.
Highlights
The classical major histocompatibility complex (MHC) molecules are highly polymorphic glycoproteins which play a central role in adaptive immunity by capturing and presenting peptide antigens to the T-cell receptor (TCR) expressed on T lymphocytes.[1]
This review summarizes the literature which has examined the potential of anti-human leukocyte antigens (HLA) antibody in allo-sensitized patients to cross-react with porcine cells
The prospects for clinical xenotransplantation have improved significantly due to recent increases in preclinical nonhuman primate xenograft survival
Summary
The classical major histocompatibility complex (MHC) molecules are highly polymorphic glycoproteins which play a central role in adaptive immunity by capturing and presenting peptide antigens to the T-cell receptor (TCR) expressed on T lymphocytes.[1]. Recent analysis suggests that stringent patient cross-matching and/ or elimination of a limited set of specific porcine class I swine leukocyte antigens (SLA) alleles can further minimize anti-pig reactivity such that future clinical xenotransplantation may be appropriate even for highly sensitized patients.
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