Fucosyl transferase (H) transgenic heart transplants to Gal-/- mice.
BACKGROUND
We have previously described the rejection of Gal+ mouse hearts by mice lacking Gala(1,3)Gal (Gal-/-) and demonstrated this to be a model of xenogeneic hyperacute rejection (HAR) which would occur in pig-to-human/primate xenotransplantation, where Gal+ antibody (Ab) and complement (C') mediate HAR. To reduce the amount of Gal present we used fucosyl transferase (H) as a transgene, H transferase competes for the same substrate as Gal transferase and reduces Gal expression by >90%.


METHODS
Gal-/- mice received a heart graft from C57BL/6 Gal+ or H transgenic mice and additional Gal Ab and C' provided; HAR was monitored by direct observation for up to 90 min, or by palpation thereafter. When grafts were rejected they were examined macro- and microscopically.


RESULTS
H transgenic mice were used as donors to Gal-/- mice; it was found that: 1) C57BL/6 or H transgenic hearts were not rejected by Gal-/- recipients within 90 min in the absence of additional Gal Ab. 2) If additional Gal Ab and C' were provided as fresh normal human serum (NHS), Gal+ (C57BL/6) grafts were rejected by Gal-/- mice in approximately 34 min, whereas H transgenic hearts mostly lasted up to 17 hr, but were then rejected. The histological appearances showed features of both Arthus and Shwartzmann phenomena. 3) Mice hyperimmunized with Gal with anti-Gal titers of >1:20,000, rejected Gal+ grafts in 31 min; the survival was prolonged to 75 min with the H transgenic hearts.


CONCLUSIONS
The presence of the H transgene in donor hearts transplanted to naive Gal-/- mice delays the onset of HAR, but rejection ultimately occurs; if the mice are hyperimmune earlier rejection occurs. The expression of the H transgene alone is insufficient to avoid HAR in the Gal-/- mouse model; the presence of other transgenes and techniques will be required to give an appropriate increase in survival of pig-to-human/primate grafts.
McKenzie
I F
IF
Molecular Immunogenetics Laboratory, Austin Research Institute, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Li
Y Q
YQ
Patton
K
K
Sandrin
M S
MS
D000208:Acute Disease; D000818:Animals; D004187:Disaccharides / Q000276:immunology*; D005647:Fucosyltransferases / Q000235:genetics*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D013997:Time Factors; D019076:Transgenes; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D004187:Disaccharides; D005647:Fucosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase