Upregulation of CD59: Potential mechanism of accommodation in a large animal model

Background. Survival of ABO-mismatched kidneys with stable renal function despite the persistence of anti-ABO antibodies is called accommodation. The mechanism of accommodation is unclear, but may involve complement regulatory proteins such as CD59. The development of alpha-1,3-galactosyltransferase knock-out (GalT-KO) swine that produce anti-Gal antibodies provides a large animal model capable of determining the role of complement regulatory proteins in accommodation. Methods. ELISA and antibody fluorescence-activated cell sorting were used to examine the rate of anti-Gal antibody expression as a function of age. Major histocompatibility complex-matched kidneys were transplanted from Gal-positive MGH miniature swine to MGH GalT-KO swine with systemic immunosuppression. One recipient underwent adsorbtion of anti-Gal antibodies before transplantation. Graft survival, antibody, and complement deposition patterns and CD59 expression were determined. Results. Three animals rejected Gal-positive kidneys by humoral mechanisms. One animal with low titers of anti-Gal antibody displayed spontaneous accommodation and the animal that was treated with antibody adsorbtion also displayed accommodation. Rejected grafts had deposition of IgM, IgG, C3, and C5b-9 with low expression of CD59, whereas accommodated grafts had low deposition of C5b-9 and high expression of CD59. Retransplantation of one accommodated graft to a naive GalT-KO animal confirmed that changes in the graft were responsible for the lack of C5b-9 deposition. Conclusion. GalT-KO miniature swine produce anti-Gal antibodies and titers increase with age. These anti-Gal antibodies can cause rejection of major histocompatibility complex-matched kidneys unless accommodation occurs. CD59 up-regulation seems to be involved in the mechanism of accommodation by preventing the formation of the membrane attack complex (MAC) on the accommodated graft.