Altered Glycosylation in Donor Mice Causes Rejection of Strain-Matched Skin and Heart Grafts

Abstract

Differential protein glycosylation in the donor and recipient can have profound consequences for transplanted organs, as evident in ABO‐incompatible transplantation and xenotransplantation. In this study, we investigated the impact of altered fucosylation on graft acceptance by using donor mice overexpressing human α1,2‐fucosyltransferase (HTF). Skin and heart grafts from HTF transgenic mice were rapidly rejected by otherwise completely matched recipients (median survival times 16 and 14 days, respectively). HTF skin transplanted onto mice lacking T and B cells induced an natural killer cell–mediated innate rejection crisis that affected 50–95% of the graft at 10–20 days. However, in the absence of adaptive immunity, the residual graft recovered and survived long‐term (>100 days). Experiments using “parked” grafts or MHC class II‐deficient recipients suggested that indirect rather than direct antigen presentation plays a role in HTF skin graft rejection, although the putative antigen(s) was not identified. We conclude that altered glycosylation patterns on donor tissue can trigger a powerful rejection response comprising both innate and adaptive components. This has potential implications for allotransplantation, in light of increasing recognition of the variability of the human glycome, and for xenotransplantation, where carbohydrate remodeling has been a lynchpin of donor genetic modification.

A Genetic Modifier of the Gut Microbiome Influences the Risk of Graft-versus-Host Disease and Bacteremia After Hematopoietic Stem Cell Transplantation

“…Alternatively, differential protein glycosylation might have a direct effect on alloreactivity. Recent xenotransplantation studies have suggested that variable glycosylation in the host modifies graft rejection in solid-organ transplantation mouse models [33]. The data reported in this study indicate an important role for FUT2 genotype in transplantation outcomes.…”

Recall features and allorecognition in innate immunity

“…(Fig. 3b) [41]. Thus, increasing evidence suggests that NK cells independently or via the communication to adaptive immune responses may contribute to graft rejection.…”

Xenotransplantation literature update, January–February 2014

“…The February issue delivered the article that inspired the January commentary. Mice that overexpressed the human alpha 1,2 fucosyltransferase (HTF) gene were used as donors for skin grafts to blood‐group‐matched mice and aggressively rejected . When skin grafts from HTF transgenic mice were transplanted onto T‐ and B‐cell‐deficient mice, nearly all were rejected but instead by an NK‐cell‐driven response.…”