IgG, but not IgM, mediates hyperacute rejection in hepatic xenografting

Abstract

We reported previously that no classical features of hyperacute rejection (HAR) could be found in liver grafts in the guinea-pig (GP)-to-rat model and that recipients died shortly after transplantation of non-immunologic causes. Thus, the GP-to-rat model is not suitable for studying the mechanisms of discordant liver xenograft rejection. In the hamster to rat model, long-term survival of a liver graft is possible, but extremely low levels of xenoreactive natural antibodies are present. To mimic a discordant situation with pre-formed IgM and IgG antibodies, we sensitized rats 1 or 5 weeks before grafting. Specific anti-hamster IgM antibodies were found in recipients sensitized at week -1 but not week -5. Anti-hamster IgG was present in all recipients, albeit considerably higher in animals sensitized 5 weeks before grafting. In these two models, we examined the mechanism of HAR of liver grafts and compared this with heart xenografts. Control heart and liver grafts were rejected 4 and 7 days after transplantation respectively. Liver grafts in recipients sensitized at week -5 showed venous congestion and bleeding after reperfusion, indicating HAR, however this was not observed after sensitization at week -1. This surprising finding was confirmed by histology. Massive extravasation, edema, and acute liver cell degradation were noticed in grafts subjected to HAR. Liver grafts of recipients sensitized at week -1 showed only minimal changes. Heart grafts were rejected hyperacutely in both sensitization models. IgG antibodies could be detected on liver grafts in the group sensitized at week -5 but not in the group sensitized at week -1. Minimal IgM depositions were found on liver grafts of animals sensitized 1 week before grafting. Rejected heart grafts from similar sensitization groups showed identical antibody depositions; only IgM depositions were massive. Complement depositions were found in all groups. These results indicate that IgG, but not IgM, mediates HAR in hepatic xenografting. Such a predominance of IgG over IgM does not exist for heart grafts.

Both IgG and IgM anti‐pig antibodies induce complement activation and cytotoxicity

“…The latter experiments may suggest that IgG and IgA anti‐Galα1–3Gal antibodies are irrelevant with respect to the induction of complement‐dependent cell death in pig cells. However, other studies reported the occurrence of HAR in association with IgG XAb, using the rat as a xenograft recipient [18,19]. Moreover, several investigators showed complement fixation and/or complement‐dependent cell death upon incubation of pig cells with purified human IgG [13,20,21], or IgA [22], whereas others could not confirm these observations [13,22,23].…”

Immunohistologic evaluation of mechanisms mediating hyperacute lung rejection, and the effect of treatment with K76‐COOH, FUT‐175, and anti‐Gal column immunoadsorption

“…The strong correlation between preperfusion antibody titers and intensity of endothelial staining for human IgG and IgM supports our contention that our method accurately reflects biologically important events in the graft. That the preperfusion IgG titer correlates better with survival than does that for IgM suggests that the former may contribute significantly to the pathogenesis of HALR, as has been suggested for guinea pig‐to‐rat liver transplant model [28]. Alternatively, IgM may be more important mechanistically, as has been suggested for the heart [29] and other organs, and the degree of depletion we achieved is simply inadequate to demonstrate this association.…”

No functional benefit for hDAF-transgenic rat livers despite protection from tissue damage following perfusion with human serum

“…In xenogeneic perfusion of the isolated normal liver with human whole blood, no hyperacute rejection (HAR) has been shown [2]. Xenotransplantation of the normal liver in a discordant rodent model showed no HAR [20]; however, in a pig-to-baboon model HAR has been established [ l l , 161 An immediate decrease of xenoreactive natural antibodies and complement in xenogeneic liver perfusion has been established in several reports [4, 71, the effect of which was not always seen on histological examination [2], as we showed in this study. However, it is known, that pig livers expressing hDAF on the endothelial cell surface exhibit less tissue damage, down-regulate complement activation and thereby the release of some cytokines during the humoral reaction [12, 141.…”