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REACTIVE OXYGEN SPECIES SYNTHETIC CATALYTIC SCAVENGERS FOR PREVENTION OF ALLOGRAFT REJECTION.
Georges Tocco, Ph.D., Akyiama Yoshinobu, M.D, Takunori Tanaka, M.D., Roma Patel, M.D., Yoshiko Iwamoto, B.S. and Gilles Benichou, Ph.D.. Boston MA, USA, Massachusetts General Hospital / Harvard Med School, 02114, Surgery/ Transplantation Unit.
The extent of highly reactive oxygen species (ROS) contribution in the rejection of transplanted tissues is not fully understood. We studied the effects of scavengers of ROS on the rejection of fully allogenic allografts in mice. Salen manganese complexes, which exhibit superoxide dismutase and catalase activities were used.as scavengers of ROS. Various analogs were tested for their potential role in preventing/delaying skin graft rejection or acute or chronic heart and corneal graft rejection. 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 a 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.