Role of graft interleukin-10 expression in the tolerogenicity of neonatal skin allografts.

Abstract

Allografts of skin from neonatal donors survive longer than those from adult donors and can induce tolerance in mice that are treated with short-term immunosuppression. Neonatal (< or =24 hr old) epidermal cells (EPC) secrete high levels of interleukin-(IL) 10 and include abundant class II- immature Langerhans cells (LC). In this study, the role of IL-10 in the tolerogenicity of neonatal skin grafts was examined. After a preliminary experiment established that tolerogenesis by neonatal grafts could be supported by monoclonal antilymphocyte antibodies, B10.A(5R) recipients were immunosuppressed with anti-CD4 plus anti-CD8 (days 0, +2) and adult C57B1/6 bone marrow cells (day +7). Recipients were grafted with adult or neonatal C57B1/6 skin from wild-type or IL-10 deficient ("knockout" donors). EPC from wild-type and knockout neonatal skin were compared by flow cytometry, before and after 48 hr culture, to adult cells in terms of class II and costimulatory molecule expression. Grafts from knockout neonates survived longer than those from adult donors (median survival, MST=81 vs. 61 days), but not as long as those from wild-type neonates (MST=100 days; P<0.05). As with normal neonatal EPC, neonatal knockout EPC expressed little class II antigen. Both types of neonatal EPC acquired class II in culture, and up-regulated CD80 and CD86 in an adult pattern, but failed to up-regulate class II antigen to the high level seen among cultured adult cells. The tolerogenicity of neonatal skin grafts derives in part from natural expression of IL-10 by the graft. Another possible contribution to tolerogenicity may be the inability of neonatal antigen presenting cells to up-regulate class II fully. Low expression of class II by neonatal cells is not attributable to epidermal IL-10 secretion.