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Fetal tissue is considered to be immune privileged and is under extensive investigation as a source of tissue for transplantation. In this paper, we analyzed the immune properties of human fetal and neonatal skin before and after transplantation to severe combined immunodeficient (SCID) mice. Using a human peripheral blood mononuclear cell reconstituted SCID (huPBMC-SCID) mouse model of allograft rejection, we compared the immune response to transplanted fetal and neonatal skin.We analyzed human fetal (55–122 days of gestation) and neonatal skin samples by routine histology and immunohistochemistry for the expression of (MHC class I and II antigens before and after transplantation to SCID mice. After transplantation, we injected the mice with huPBMCs and analyzed the survival of neonatal and fetal skin grafts both visually and microscopically.We detected no class II expression in fetal skin of all gestational ages and only weak class I expression after 89 days compared with abundant class I and II expression in neonatal skin before transplantation. When transplanted to SCID mice, fetal skin grafts differentiated and expressed class I and II, but the levels were lower than neonatal grafts. In mice injected with huPBMCs, rejection of neonatal grafts started on day 5, and by day 9 all grafts were rejected. In contrast, rejection of fetal skin grafts was significantly delayed. Rejection started on day 13 and was complete by day 23 (P <0.00005). Histology sections from the rejected grafts showed marked CD3+ T cell infiltration in the human skin with a sharp demarcation between the human and mouse skin, with no T-cell infiltration in the mouse skin. CD4+ and CD8+ T cells were present in the rejected sites in similar densities.Our results show that fetal skin differentiates and expresses increased amounts of MHC class I and class II antigens when transplanted to SCID mice. However, these levels are much lower than the levels found in neonatal skin. We demonstrate that the survival of human fetal skin allografts is markedly prolonged compared with that of neonatal skin grafts in the huPBMC-SCID mouse model. Our results support the hypothesis that low levels of MHC antigen expression lead to a delay in the rejection of fetal skin and further demonstrate the utility of the huPBMC-SCID mouse model to investigate the molecular and cellular mechanisms of the immune response to human fetal tissues.