Induction of donor-specific tolerance to cardiac xenografts in utero

Background: Problems associated with heart transplantation, such as shortage of suitable organs and the side effects of immunosuppressive therapy, are especially serious for patients in the pediatric age group. Induction of donor-specific immunologic tolerance without immunosuppressive drugs would be ideal for clinical organ transplantation. In this study, we used a vascularized cardiac xenograft model to achieve donor-specific unresponsiveness without immunosuppression by manipulating the intrauterine immune response. Methods: Lewis rats and Golden Syrian hamsters were used as the recipients and donors, respectively. Donor bone marrow cells (15 x 10(6) in 0.05 mt) were injected into each fetus of pregnant Lewis rats on days 9 (n = 2) and 16 (n = 2) of gestation. Donor hearts were heterotopically transplanted into each surviving (n = 8, n = 5) fetus of the Lewis rats at 8 weeks of age. Donor hearts were also transplanted into untreated rats as controls (n = 8). Results: The mean cardiac xenograft survival time was 2.5 +/- 0.5, 7.4 +/- 4.1, and 2.8 +/- 0.8 days in the control group, gestational day 9 group, and gestational day 16 group, respectively. Chromosomal analysis of the day 9 group showed Golden Syrian hamster chromosomes as well as Lewis rat chromosomes. Conclusions: Cardiac xenograft survival was significantly prolonged by intrauterine exposure to xenograft bone marrow cells on day 9 but not on day 16 of gestation. Cardiac xenograft survival and chromosomal analysis of the recipient bone marrow suggested that chimerism was achieved between Golden Syrian hamsters and Lewis rats. Cardiac xenotransplantation may be possible by induction of donor-specific tolerance in utero.