1.1
#15
PROLONGATION OF SKIN AND HEART ALLOGRAFT SURVIVAL BY SYNTHETIC CATALYTIC SCAVENGERS OF REACTIVE OXYGEN SPECIES.
Georges Tocco Ph.D. , Ben Illigens M.D. , Yoshiko Iwamoto B.S. , Yoshinobu Akiyama M.D. and Gilles A. Benichou, Ph.D. D.Sc . Boston MA, Massachusetts General Hospital, 02114, Surgery .

---

The role of highly reactive oxygen species (ROS) in the rejection of transplanted tissues is unknown. Here, we studied the effects of scavengers of ROS on the rejection of fully allogeneic skin grafts in mice. To test this, we used a series of synthetic compounds (EUK-8, -134 and 189), known as salen manganese complexes, which exhibit superoxide dismutase and catalase activities. We showed that pre-transplant treatment of BALB/c recipients with salen manganese complexes significantly delayed the rejection of fully allogeneic heart and skin from C57BL/6 donors. ELISPOT analysis of alloimmune response in EUK treated mice revealed a significant reduction of the frequency of type 1 cytokine (pro-inflammatory) producing T cells, while the number of activated T cells producing type 2 cytokines was elevated. Moreover, anti-oxidative treatment of graft recipients resulted in a profound inhibition of their donor-specific cytotoxic T cell response. Additionally, in vitro analysis demonstrated the ability of these compounds to reduce MLR. Taken together, these results indicate that salen manganese complexes mediate their effect on graft rejection both by reducing the susceptibility of graft tissue to ROS-mediated injury and by exerting an anti-inflammatory effect as well as potential tolerogenic effect in recipients. These observations demonstrate the contribution of ROS in transplant rejection and suggest that utilization of anti-oxidative compounds may represent a novel and promising strategy to prolong the survival of allogeneic transplants.