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

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 caus es. Thus, the GP-to-rat model is not suitable for studying the mechanisms o f discordant liver xenograft rejection. In the hamster to rat model, long-t erm survival of a liver graft is possible, but extremely low levels of xeno reactive natural antibodies are present. To mimic a discordant situation wi th pre-formed IgM and IgG antibodies, we sensitized rats 1 or 5 weeks befor e grafting. Specific anti-hamster IgM antibodies were found in recipients s ensitized at week -1 but not week -5. Anti-hamster IgG was present in all r ecipients, albeit considerably higher in animals sensitized 5 weeks before grafting. In these two models, we examined the mechanism of HAR of liver gr afts and compared this with heart xenografts. Control heart and liver graft s were rejected 4 and 7 days after transplantation respectively. Liver graf ts in recipients sensitized at week -5 showed venous congestion and bleedin g after reperfusion, indicating HAR, however this was not observed after se nsitization at week -1. This surprising finding was confirmed by histology. Massive extravasation, edema, and acute liver cell degradation were notice d 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 graft s in the group sensitized at week -5 but not in the group sensitized at wee k -1. Minimal IgM depositions were found on liver grafts of animals sensiti zed 1 week before grafting. Rejected heart grafts from similar sensitizatio n groups showed identical antibody depositions; only IgM depositions were m assive. Complement depositions were found in all groups. These results indi cate that IgG, but not IgM, mediates HAR in hepatic xenografting. Such a pr edominance of IgG over IgM does not exist for heart grafts.