title: 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.
authors: Immunology Research Centre, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.
authors: H
authors: H
authors: Gock
authors: L J
authors: LJ
authors: Murray-Segal
authors: A C
authors: AC
authors: Winterhalter
authors: A
authors: A
authors: Aminian
authors: G T C
authors: GT
authors: Moore
authors: S J
authors: SJ
authors: Brown
authors: A J F
authors: AJ
authors: d'Apice
authors: P J
authors: PJ
authors: Cowan
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006084:Graft Rejection / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008285:Major Histocompatibility Complex / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011379:Prognosis; D012307:Risk Factors; D016038:Skin Transplantation / Q000009:adverse effects*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D014183:Transplantation, Heterologous / Q000009:adverse effects*; D014184:Transplantation, Homologous; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D005647:Fucosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase
keywords: Animal models; NK cells; O blood group; innate immunity; skin grafts; transgenic mouse