Prolongation of skin allograft survival is associated with reduced Th1 cytokine responses in the WKY -> F344 rat model

Background. We have reported previously that F344 rats develop a spontaneou s tolerance to WKY lung allografts and show long-term retention of donor-sp ecific skin grafts placed 35 days after lung transplantation. In this study , we investigated the immunologic mechanisms that may be responsible for th e prolonged skin graft survival in animals tolerized with lung allografts. Methods. In the rejection group, WKY skin grafts were placed on normal F344 rats, whereas, in the tolerance group, the skin grafts were placed on F344 rats that had received a WKY lung transplant 35 days before skin grafting. Th1 (interleukin [IL]-2 and interferon-gamma [IFN-gamma]) and Th2 (IL-4 an d IL-10) cytokine as well as transforming growth factor-beta 1 mRNA express ion in skin grafts and in draining lymph nodes were determined by reverse t ranscription-polymerase chain reaction. Macrophage and lymphocyte infiltrat ion in skin grafts and the number of Langerhans cells in epidermal sheets o f the grafts were examined by immunohistochemistry, Results. IL-2 and IFN-gamma mRNA expression was significantly decreased in both the skin grafts and the draining lymph nodes of the tolerance group, c ompared to the rejection group, whereas IL-10 and transforming growth facto r-beta 1 mRNA expression was similar in both groups and IL-4 mRNA was rarel y detected. Decreased and delayed CD8(+), macrophage, and natural killer ce ll infiltration in the skin grafts from the tolerance group was also detect ed, Similar reduction in the number of Langerhans cells in the epidermis of the grafts from both groups was seen on day 1 after skin grafting, and the reafter the number remained stable in both groups. Conclusions. Reduced expression of Th1 cytokines and decreased infiltration of CD8(+) cells, macrophages, and natural killer cells in the skin grafts may be responsible for prolongation of skin graft survival in the tolerance group.