• Cardiac;
  • neonate;
  • non-specific;
  • tissue-specific;
  • tolerance

Neonatal tolerance is exclusively donor-specific when assessed by skin allograft survival and in vitro alloreactivity assays. In contrast, we reported previously that acceptance of primarily vascularized cardiac allografts was not donor-specific in C3H/He (C3H, H-2k) mice treated as neonates with BALB/c-derived (BALB, H-2d) lymphohematopoietic cells, but included third-party C57BL/10 (B10, H-2b) allografts. The present study examined whether this unusual pattern is limited to heart grafts in this strain combination, and defined the relative importance of the donor cell H-2d haplotype for third-party cardiac allograft acceptance. C3H neonates were injected with (C3HxBALB)F1 bone marrow and spleen cells. Tolerance was assessed at age 8–10 weeks by transplantation of heart or skin allografts from several donor strains, and by in vitro assays of proliferation and cytotoxicity. Additionally, cells from H-2d and H-2b-expressing strains on BALB or non-BALB minor histocompatibility (miH) antigen backgrounds were tested as tolerizing inocula. Prolonged survival of cardiac grafts from all donor strains was observed in neonatally treated mice, whereas skin grafting and in vitro assays demonstrated donor-specific hyporesponsiveness. Both H-2d haplotype and non-H-2 miH background of graft donor and tolerizing cell donor were important to third-party cardiac allograft acceptance. These results suggest that the functional alteration in alloreactivity induced by neonatal alloantigen exposure depends partly on method of assessment.