title: Hyperacute rejection of vascularized heart transplants in BALB/c Gal knockout mice.
abstract: Pig-to-primate vascularized xenografts undergo hyperacute rejection (HAR). This results from pre-formed xenoreactive antibodies directed against galactose-alpha1,3-galactose (alphaGal) in the donor organ and activation of the complement cascade. We describe an in vivo murine model of HAR using a BALB/c mice system devoid of histocompatibility or complement differences between donor and recipient to investigate in isolation, the effects of alphaGal epitope and anti-alphaGal antibody interactions in causing rejection of vascularized heart transplants. Gal KO mice were immunized with rabbit red blood cell membranes to induce high anti-alphaGal antibody titers that were predominantly IgM by ELISA (enzyme-linked immunosorbent assay). When alphaGal-expressing mice hearts were transplanted heterotopically into these recipients (n= 12), 67% of grafts rejected within 24 h, the majority within 16 h with histological features of HAR. In contrast, none of the grafts in the non-immunized Gal KO recipient control group (n=11) underwent HAR. Interestingly, approximately 50% of the remaining grafts in both the immunized and non-immunized Gal KO recipient group were rejected between 7 and 27 days by a rejection process characterized by a dense infiltrate of macrophage/monocytes, perivascular cuffing and tissue destruction similar to recent descriptions of delayed xenograft rejection (DXR). In addition, some grafts (21.5%) continued to survive in the immunized Gal KO recipients despite the presence of anti-alphaGal antibody and normal complement activity and these showed well-preserved myocardium when harvested whilst still functioning well at days 30 or 90. No rejection was seen when Gal KO donors were used in this system (n=4), nor when alphaGal-expressing BALB/c hearts were transplanted into alphaGal-expressing BALB/c recipients (n=5). This in vivo small animal model offers the opportunity to test a variety of strategies to overcome HAR prior to more resource intensive pig-to-primate studies, and may provide insights into the processes similar to DXR and accommodation.
authors.affiliation: Immunology Research Center, St Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Gock
authors.forename: E
authors.initials: E
authors.lastname: Salvaris
authors.forename: L
authors.initials: L
authors.lastname: Murray-Segal
authors.forename: P
authors.initials: P
authors.lastname: Mottram
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.forename: M J
authors.initials: MJ
authors.lastname: Pearse
authors.forename: D J
authors.initials: DJ
authors.lastname: Goodman
authors.forename: P J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: A J
authors.initials: AJ
authors.lastname: d'Apice
mesh_terms: D000208:Acute Disease; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D001160:Arterioles / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004187:Disaccharides / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D017707:Erythrocyte Transfusion; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D011817:Rabbits
chemical_list: D000910:Antibodies, Heterophile; D004187:Disaccharides; D000939:Epitopes; C055075:galactosyl-(1-3)galactose; D005700:Galactosyltransferases