FTY720 treatment in skin allograft rejection Commodaro AG et al. A member of the IL-12 family of cytokines, namely IL-27, has been shown to cause the immune-specific suppression of IL-17 secretion by down-regulating retinoid orphan nuclear receptor C expression. This inhibition is associated with the induction of the intracellular signaling factor STAT1 and the suppression of cytokine signaling protein 1 (15). Investigations of the Treg-Th17 axis aim to identify poten- tial pharmacological targets to promote graft acceptance. The new compound FTY720 binds to S1P (sphingosine-1 phosphate) receptors, causing lymphocytes to be seques- tered in secondary lymphoid organs. In addition, FTY720 inhibits the egress of lymphocytes from the thymus and secondary lymphoid tissues into the periphery, thereby preventing the migration of lymphocytes to inflammatory sites (16,17). Some additional mechanisms of action have been proposed for FTY720, such as its anti-proliferative effect on T cells through the augmentation of regulatory T cell activity and secretion of suppressive cytokines (18-20). FTY720 has also been shown to cause the suppression of IL- 17 secretion by Th17 cells in vitro (15). Jin et al. (21) showed that, although FTY720 improved CD4CD25Foxp3 expression after skin transplantation, the CLINICS 2012;67(7):805-813 monotherapy was not sufficient to prevent rejection. How- ever, when MR1 (anti-CD154 mAb) was administered in combination with FTY720, skin allograft survival increased. Interestingly, the expression of CD4CD25Foxp3 was similar when FTY720 monotherapy was compared with FTY720+ MR1. These findings suggest that mechanisms other than CD4CD25Foxp3 expression occur during allograft accep- tance. To further understand the process of graft accep- tance/rejection, we evaluated skin allograft survival and associated events following treatment with FTY720. MATERIALS AND METHODS Experimental groups Mice were cared for in accordance with the Principles of Laboratory Animal Care (NIH publication 86-23, revised 1985) and the regulations of the Brazilian Committee on Animal Experimentation. The project was submitted to and approved by the Animal Ethic Committee of UNIFESP Federal University of Sa˜o Paulo (protocol 0125/08). Eight- to ten-week-old male (C57BL/6xBALB/c) F1 and C57BL/6 mice were used as donors for and recipients of Figure 1 - FTY720 treatment prolongs mouse skin allograft survival. F1 (BALB/c x C57BL/6) mice were donors to C57BL/6 recipients, and skin allograft rejection was determined macroscopically when the graft reached a necrosis level of 90%. A - Kaplan-Meier curve of skin allograft survival showing that FTY720 treatment significantly increased the survival of F1 (BALB/c x C57BL/6) skin allografts in the C57BL/6 recipients. B - The macroscopic signs of rejection were observed as early as day 7 in transplanted, non-treated (Tx) mice. C - Rejection signs occurred later in the transplanted, FTY720-treated (Tx+FTY) mice. 806