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 naïve GalT-KO animal confirmed that changes in the graft were responsible for the lack of C5b-9 deposition.


CONCLUSIONS
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.
Griesemer
Adam D
AD
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Okumi
Masayoshi
M
Shimizu
Akira
A
Moran
Shannon
S
Ishikawa
Yoshinori
Y
Iorio
Justin
J
Arn
J Scott
JS
Yamada
Kazuhiko
K
D000818:Animals; D030801:Animals, Genetically Modified; D001402:B-Lymphocytes / Q000276:immunology; D018957:CD59 Antigens / Q000235:genetics*; D005700:Galactosyltransferases / Q000235:genetics / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods; D016030:Kidney Transplantation / Q000276:immunology*; D008285:Major Histocompatibility Complex; D023421:Models, Animal; D013552:Swine; D013556:Swine, Miniature; D015854:Up-Regulation
D018957:CD59 Antigens; D005700:Galactosyltransferases