Decay-Accelerating Factor Prevents Acute Humoral Rejection Induced by Low Levels of Anti-αGal Natural Antibodies

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Abstract
Hyperacute and delayed vascular rejection due to natural antibodies (NAb) present major obstacles in pig-to-primate xenotransplantation. Although “supraphysiologic” expression of human complement regulatory proteins (CRPs) can prevent hyperacute rejection in discordant xenogenic recipients, their physiologic role in the homologous setting is undefined. We have evaluated the effect of the absence of decay-accelerating factor (DAF) on cardiac allograft rejection in the presence of different levels of antidonor antibodies (Ab). DAF1-deficient (DAF KO; B6129F2 H-2b) mice were used as heart graft donors to α1,3-galactosyltransferase deficient (GalT KO; B6, H-2b) recipients. Heterotopic heart grafting was performed with or without presensitization. Graft survival, histology, and anti-αGal Ab levels were monitored. DAF knockout (KO) but not wild-type (WT) grafts showed hyperacute or acute humoral rejection in nonsensitized GalT KO mice with low levels of anti-αGal IgM NAb. However, humoral rejection of both DAF KO and DAF WT donor grafts occurred in presensitized GalT KO recipients. The expression of DAF prevents hyperacute rejection in mice with low titers of anti-αGal antibody. These studies demonstrate the physiologic role of DAF in preventing humoral rejection in the presence of low levels of NAb and have implications for transplantation of discordant vascularized xenografts.