TOLEROGENIC BEHAVIOR OF SKIN ALLOGRAFTS FROM NEONATAL MICE

Neonatal skin allografts can be tolerogenic when transplanted to appro priately immunosuppressed hosts. Single grafts of neonatal skin surviv e longer than adult skin grafts when recipients are treated with antil ymphocyte serum (ALS) and donor bone marrow cells (BMC). Neonatal skin grafts can also prolong the survival of adult grafts of the same dono r strain simultaneously cotransplanted with the neonatal grafts. To pr obe the mechanisms involved in this cotransplantation phenomenon, we d elayed placement of the neonatal cotransplants relative to grafting wi th adult skin. Neonatal allografts placed either 7-9 days or 14 days a fter grafting with adult skin significantly prolonged adult graft surv ival in mice treated with ALS and BMC. However, day 0-placed neonatal cotransplants must remain on the recipient for > 2 weeks to prolong ad ult graft survival. Removal of cotransplants from ALS- and BMC-treated recipients after 7 or 14 days abrogated the cotransplantation effect. If left in place until day 21, neonatal cotransplants could significa ntly prolong adult graft survival, but did not induce the long-term gr aft survival observed in approximately 50% of the recipients whose cot ransplants were not removed. Cotransplant removal after 1 year did not affect subsequent adult graft survival. Additionally, cotransplants w ere removed from recipients either on day 14 or from longterm graft-be aring mice and retransplanted to other ALS/BMC-treated recipients. The se retransplanted grafts were unable to prolong survival of adult graf ts on the new recipients. After transplant, but not before transplant, cyclophosphamide treatment of recipients prevented expression of the cotransplant effect in ALS-treated mice. However, recipient splenectom y greater than or equal to 1 week before grafting did not interfere wi th the effect. These results reflect on the contributions of the donor tissue, and the recipients' response, to the tolerogenic signals that permit a neonatal cotransplant to prolong adult graft survival.