Porcine Sialoadhesin: A Newly Identified Xenogeneic Innate Immune Receptor

Abstract

Extracorporeal porcine liver perfusion is being developed as a bridge to liver allotransplantation for patients with fulminant hepatic failure. This strategy is limited by porcine Kupffer cell destruction of human erythrocytes, mediated by lectin binding of a sialic acid motif in the absence of antibody and complement. Sialoadhesin, a macrophage restricted lectin that binds sialic acid, was originally described as a sheep erythrocyte binding receptor. Given similarities between sialoadhesin and the unidentified macrophage lectin in our model, we hypothesized porcine sialoadhesin contributed to recognition of human erythrocytes. Two additional types of macrophages were identified to bind human erythrocytes - spleen and alveolar. Expression of sialoadhesin was confirmed by immunofluorescence in porcine tissues and by flow cytometry on primary macrophages. A stable transgenic cell line expressing porcine sialoadhesin (pSn CHO) bound human erythrocytes, while a sialoadhesin mutant cell line did not. Porcine macrophage and pSn CHO recognition of human erythrocytes was inhibited approximately 90% by an anti-porcine sialoadhesin monoclonal antibody and by human erythrocyte glycoproteins. Furthermore, this binding was substantially reduced by sialidase treatment of erythrocytes. These data support the hypothesis that porcine sialoadhesin is a xenogeneic receptor that mediates porcine macrophage binding of human erythrocytes in a sialic acid-dependent manner.

Lung xenotransplantation

“…In addition to releasing pro-inflammatory and pro-coagulant factors, pig alveolar lung and spleen macrophages and liver Kuppfer cells bind to and phagocytose human blood cells through innate cellular carbohydrate recognition by the porcine lectin sialoadhesin (23). …”

Pretransplant replacement of donor liver grafts with recipient Kupffer cells attenuates liver graft rejection in rats

“…However, pretreatment of donors would be acceptable for xenotransplantation. In xenotransplantation, porcine KCs directly recognize a sialic acid motif on human glycophorin A and destroy human erythrocytes . We speculate that the strategy of KC replacement might be useful in making clinical xenotransplant trials feasible.…”

Differential Role of B Cells and IL-17 Versus IFN-γ During Early and Late Rejection of Pig Islet Xenografts in Mice

“…While literature on carbohydrate-mediated skewing of Th17 differentiation is predominantly from models of infection(46, 47), it has recently been shown that such a skewing may also play a role in transplantation rejection such as graft-versus-host disease (GVHD)(48). Recognition of xenogeneic carbohydrates by lectin receptors has been described in discordant xenogeneic transplantation models to promote phagocytosis of xenogeneic (human) erythrocytes and platelets by porcine macrophages(49, 50). Interestingly, lectin receptor on CD4 T cells has also been associated with a propensity of their differentiation towards Th17 cells(51) and an increased risk for GVHD(52).…”