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.
