Fucosyl transferase (H) transgenic heart transplants to Gal-/- mice

Background, We have previously described the rejection of Gal(+) mouse hear ts by mice lacking Gal alpha>(*) over bar * (1,3)Gal (Gal-/-) and demonstra ted 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 th e same substrate as Gal transferase and reduces Gal expression by >90%. Methods. Gal-/- mice received a heart graft from C57BL16 Gal(+) or H transg enic mice and additional Gal Ab and C' provided; HAR was monitored by direc t observation for up to 90 min, or by palpation thereafter. When grafts wer e 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-/- recipi ents within 90 min in the absence of additional Gal Ab, 2) If additional Ga l Ab and C' were provided as fresh normal human serum (NHS), Gal(+) (C57BL1 6) grafts were rejected by Gal-/- mice in similar to 34 min, whereas H tran sgenic hearts mostly lasted up to 17 hr, but were then rejected. The histol ogical appearances showed features of both Arthus and Shwartzmann phenomena . 3) Mice hyperimmunized with Gal with anti-Gal titers of > 1:20,000, rejec ted Gal(+) grafts in 31 min; the survival was prolonged to 75 min with the H transgenic hearts. Conclusion. 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 t he 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.