YC-1 Prevents Dendritic Cell Maturation and Prolongs Groin Skin Flap Allotransplantation Survival

Dendritic cells (DCs) are the most important antigen-presenting cells (APC) of the immune system. They function either to stimulate or to inhibit immune responses. Exploiting the immune-regulatory capacities of dendritic cells, therefore, holds great promise for prevention of transplant rejection. Recently, it has been suggested that cyclic nucleotides regulate certain steps of DC maturation. The authors then investigated the effect of YC-1, a guanylate cyclase (GC) activator, on maturation of human monocyte-derived dendritic cells (MDDC) and in prevention of transplant rejection in composite tissue allotransplantation.

Groin skin flap allotransplantations across the MHC barrier between Brown Norway donors (BN, RT1n) and Lewis recipients (LEW, RT1l) were used. Animals were randomized into four groups: Group 1, isograft control (n = 7); Group 2, allograft control (n = 6); Groups 3 and 4, experimental groups receiving YC-1 (0.2 mg/kg, n = 10) and dYC-1 (0.5 mg/kg, n = 6) for 7 days. Mature dendritic cells were derived from peripheral blood monocytes in the presence of IL-4 and GM-CSF, followed by exposure with LPS. The levels of mature DC markers (CD86 and HLA-DR) were evaluated by flow cytometry.

YC-1-treated recipients had a moderate survival prolongation to 12.5 ± 0.72 D (YC-1, 0.2 mg/kg) and 13.5 ± 1.02 D (YC-1, 0.5 mg/kg) compared with the allograft control group (8.33 ± 1.02 D). Consistent with clinical observation, histology results also showed reduction of lymphocytic infiltration and necrosis in the YC-1-treated group. Furthermore, YC-1 antagonized LPS-induced morphology change and surface maturation marker expression of CD86 and HLA-DR on MDDC were found.

These results suggest that YC-1 treatment can prolong groin skin flap allotransplantation survival in the recipient, possibly through suppression of dendritic cell maturation.