Altered glycosylation in donor mice causes rejection of strain-matched skin and heart grafts

Hilton Gock, Lisa J Murray-Segal, Adam C Winterhalter, Atousa Aminian, Gregory Thomas Charles Moore, Steven J Brown, Anthony J F D'Apice, Peter J Cowan

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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 alpha1,2-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.
Original languageEnglish
Pages (from-to)797 - 805
Number of pages9
JournalAmerican Journal of Transplantation
Volume14
Issue number4
DOIs
Publication statusPublished - 2014

Cite this

Gock, H., Murray-Segal, L. J., Winterhalter, A. C., Aminian, A., Moore, G. T. C., Brown, S. J., ... Cowan, P. J. (2014). Altered glycosylation in donor mice causes rejection of strain-matched skin and heart grafts. American Journal of Transplantation, 14(4), 797 - 805. https://doi.org/10.1111/ajt.12634
Gock, Hilton ; Murray-Segal, Lisa J ; Winterhalter, Adam C ; Aminian, Atousa ; Moore, Gregory Thomas Charles ; Brown, Steven J ; D'Apice, Anthony J F ; Cowan, Peter J. / Altered glycosylation in donor mice causes rejection of strain-matched skin and heart grafts. In: American Journal of Transplantation. 2014 ; Vol. 14, No. 4. pp. 797 - 805.
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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 alpha1,2-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.",
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Gock, H, Murray-Segal, LJ, Winterhalter, AC, Aminian, A, Moore, GTC, Brown, SJ, D'Apice, AJF & Cowan, PJ 2014, 'Altered glycosylation in donor mice causes rejection of strain-matched skin and heart grafts', American Journal of Transplantation, vol. 14, no. 4, pp. 797 - 805. https://doi.org/10.1111/ajt.12634

Altered glycosylation in donor mice causes rejection of strain-matched skin and heart grafts. / Gock, Hilton; Murray-Segal, Lisa J; Winterhalter, Adam C; Aminian, Atousa; Moore, Gregory Thomas Charles; Brown, Steven J; D'Apice, Anthony J F; Cowan, Peter J.

In: American Journal of Transplantation, Vol. 14, No. 4, 2014, p. 797 - 805.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Aminian, Atousa

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AU - Brown, Steven J

AU - D'Apice, Anthony J F

AU - Cowan, Peter J

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