Anti-gal Antibody-mediated Allograft Rejection In α1,3-galactosyltransferase Gene Knockout Mice: A Model of Delayed Xenograft Rejection
1998
Background. The key role of anti-galactoseal,3-galactose (anti-αGal) xenoantibodies in initiating hyperacute xenograft rejection has been clearly demonstrated using a variety of in vitro and in vivo approaches. However, the role of anti-αGal antibodies in mediating post-hyperacute rejection mechanisms, such as antibody-dependent cellular cytoxicity, remains to be determined, primarily because of the lack of a small animal model with which to study this phenomena. Methods. Hearts from wild-type mice were transplanted heterotopically into α1,3-galactosyltransferase knockout (Gal KO) mice, which like humans develop antibodies to the disaccharide galactoseα1,3-galactose (Gal). At the time of rejection, hearts were examined histologically to determine the mechanism of rejection. Results. Hearts from wild-type mice transplanted into high-titer anti-αGal recipients were rejected in 8-13 days. Histological examination demonstrated a cellular infiltrate consisting of macrophages (80-90%), natural killer cells (5-10%), and T cells (1-5%). In contrast, wild-type hearts transplanted into low anti-Gal titer recipients demonstrated prolonged (>90 day) survival. However, a significant proportion (30-40%) of these underwent a minor rejection episode between 10 and 13 days, but then recovered (accommodated). Conclusions. The results of this study suggest that the Gal KO mouse is a useful small animal vascularized allograft model, in which the role of anti-αGal antibody in graft rejection can be studied in isolation from other rejection mechanisms. The titer of antiαGal antibody was found to be the critical determinant of rejection. The histopathological features of rejection in this model are very similar to other models of delayed xenograft rejection, in both the timing and composition of the cellular infiltrate. The Gal KO mouse therefore provides a new rodent model, which will aid in the identification of the distinct components involved in the pathogenesis of delayed xenograft rejection.
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