Cross-Reactivity between Swine Leukocyte Antigen and Human Anti–HLA-Specific Antibodies in Sensitized Patients Awaiting Renal Transplantation

Abstract

Abstract. Xenotransplantation is increasingly viewed as a promising way to alleviate the problem of patients who have alloreactive lymphocytotoxic antibodies and therefore tend to accumulate on the waiting list for renal transplantation. One barrier to xenotransplantation in these patients could be the hyperacute or acute vascular rejection as a result of preexisting anti-HLA antibodies that recognize swine leukocyte antigens. The cross-reactivity of sera from 98 patients with pig lymphocytes was studied by flow cytometry. After absorption of xenoreactive natural antibodies (XNA), isotype, class, and antibody specificity causing a positive cross-match (XM) were determined. For nonsensitized patients, all of the antibody binding to pig lymphocytes was due to XNA, which were removed by pig red blood cells absorption. In contrast, in sensitized patients, after removal of XNA, pig lymphocyte XM remained positive. There was no correlation between antibody binding to pig lymphocytes and Ig isotype (IgG or IgM) or HLA class-specific antibodies. For testing evidence that class II-specific antibodies were responsible for antibody binding to pig lymphocytes, HLA class I-specific antibodies were absorbed with pooled human platelets. It was confirmed that HLA class II-specific antibodies were responsible for the positive pig XM, but the strength of the positive XM was weaker than the strength caused by HLA class I-specific antibodies. Sera with multiple specificities (plurispecific sera) displayed a greater frequency of cross-reactivity with swine leukocyte antigens (P Ͻ 0.05). Seven of 11 highly immunized patients without cross-reactivity IgG with porcine lymphocytes showed positive XM before an IgM was used. The results demonstrate the cross-reactive nature of HLA antibodies and therefore point out the need to perform a prospective XM after absorption of XNA in presensitized individuals.

Cross‐reactivity between decellularized porcine corneal lamellae for corneal xenobridging and subsequent corneal allotransplants

“…It has been well documented that swine leukocyte antigen (SLA) and human leukocyte antigen (HLA) share considerable sequence homology . Although some reports argue that pre‐existing HLA‐reactive antibodies can be cross‐reactive with SLA and human T cells can recognize SLA antigens via direct and indirect pathways , current reports indicate that sensitization to an allograft would not be detrimental to a subsequent pig xenograft . On the other side of the coin, whether a subsequent allograft transplanted into a patient with a bridging xenograft would be at increased risk of humoral or cellular rejection through sensitization by the primary xenograft is a still considerable debating issue.…”

Is sensitization to pig antigens detrimental to subsequent allotransplantation?

“…Naziruddin et al, 1998 30 Taylor et al, 1998 31 Barreau et al, 2000 35 Popma et al, 2000 36 Mulder et al, 2000 37 Oostingh et al, 2002 38 Varela et al, 2003 39 Mulder et al, 2010 42 Martens et al, 2017 32 HLA sensitization is not detrimental Bartholomew et al, 1997 34 Wong et al, 2006 40 Hara et al, 2006 41 Zhang et al 29…”

The desirable donor pig to eliminate all xenoreactive antigens

“…These studies yielded conflicting results likely because of the non‐SLA xenoantigens, such as Neu5Gc and β4GalNT2‐derived antigens, increased background antibody binding making detection of SLA reactivity difficult. In addition, the presence of immunoglobulin reactive with class II SLA was indirectly measured by attempting to remove anti‐pig anti‐class I antibodies from human sera using class I HLA positive human platelets, presumably leaving only anti‐class II HLA antibodies to measure . The development of TKO pigs and the development of human cell lines expressing individual SLA alleles helped to enable a more direct analysis of the repertoire of human antibodies which bind class I and class II SLA.…”