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Hyperacute rejection of vascularized heart transplants in BALB/c Gal knockout mice
Author(s) -
Gock Hilton,
Salvaris Evelyn,
MurraySegal Lisa,
Mottram Patricia,
Han Wenruo,
Pearse Martin J.,
Goodman David J.,
Cowan Peter J.,
D'apice Anthony J. F.
Publication year - 2000
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1034/j.1399-3089.2000.00572.x
Subject(s) - xenotransplantation , transplantation , antibody , epitope , heart transplantation , complement system , immunology , in vivo , antibody titer , pathology , biology , medicine , titer , microbiology and biotechnology
Pig‐to‐primate vascularized xenografts undergo hyperacute rejection (HAR). This results from pre‐formed xenoreactive antibodies directed against galactose‐α1,3‐galactose (αGal) 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 αGal epitope and anti‐αGal antibody interactions in causing rejection of vascularized heart transplants. Gal KO mice were immunized with rabbit red blood cell membranes to induce high anti‐αGal antibody titers that were predominantly IgM by ELISA (enzyme‐linked immunosorbent assay). When αGal‐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‐αGal 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 αGal‐expressing BALB/c hearts were transplanted into αGal‐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.