Serum anti-pig antibodies as potential indicators of acute humoral xenograft rejection in pig-to-cynomolgus monkey kidney transplantation.
BACKGROUND
Hyperacute rejection of solid organ pig xenografts in nonhuman primates has been overcome by using donors transgenic for human complement regulatory proteins, but grafts are still susceptible to humoral (antibody-mediated) rejection. We investigated whether circulating xenoreactive antibodies are a useful indicator of this xenograft rejection.


METHODS
Five assays were employed in a retrospective analysis on 20 selected cynomolgus monkey recipients of renal xenografts transgenic for human decay-accelerating factor, with survival between 4 and 60 days. The assays included hemolytic and hemagglutination assays and the measurement of immunoglobulin (Ig)G and IgM binding to porcine endothelial cells and leukocytes, and to the Gal alpha 1-3Gal trisaccharide (Gal) antigen. To assess non-Gal-directed antibodies, sera were absorbed with a Gal-coated resin. A predictive value was defined as an increase in antibody levels before a decline in graft failure (>20% increase in creatinine levels) and humoral rejection in graft pathology.


RESULTS
Data on hemolytic anti-pig antibody correlated with those on IgM antibody to endothelial cells, leukocytes, and Gal. In absorbed sera IgM and IgG antibody to endothelial cells and leukocytes correlated with each other, indicative for an elicited antibody response to non-Gal antigens. Sixteen animals showed humoral rejection, and in all but two animals one or more assays was considered of predictive value. On the other hand, increased antibody levels were noted in two animals without signs of rejection in graft pathology and in two cases with cellular xenograft rejection.


CONCLUSIONS
It is recommended to use multiple assays (preferably hemolytic, anti-Gal, and anti-endothelial cell) to be able to fully monitor the peripheral antibody responses in pig-to-primate xenograft recipients.
Richards
Andrew C
AC
Imutran Ltd-A Novartis Pharma AG Company, Cambridge CB2 2YP, UK.
Davies
Hugh F S
HF
McLaughlin
Megan L
ML
Copeman
Laura S
LS
Holmes
Beverly J
BJ
Dos Santos Cruz
Gabriela
G
Bycroft
Sandhya
S
Chavez
Gilda
G
White
David J G
DJ
Schuurman
Henk-Jan
HJ
Cozzi
Emanuele
E
D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000097:blood*; D000917:Antibody Formation; D015415:Biomarkers / Q000097:blood; D018958:CD55 Antigens / Q000235:genetics; D004730:Endothelium, Vascular / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008252:Macaca fascicularis; D012189:Retrospective Studies; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D000910:Antibodies, Heterophile; D015415:Biomarkers; D018958:CD55 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M