Preventing Graft Rejection with Piceatannol

DESCRIPTION (provided by applicant): Current immunosuppressive agents enhance graft survival, however, the need for continuous use of these agents induces toxicities and renders the graft recipient susceptible to infection and neoplasias. Thus, there is a need for agents that after short treatment, alone or in combination with low doses of existing immunosuppressants, block graft rejection. Piceatannol blocks Syk and ZAP- 70, kinases critical for immune cell function. We found piceatannol in combination with a subtherapeutic concentration of CsA prolonged kidney graft survival in a stringent rat transplant model with several animals maintaining their grafts for more than 200 days. Excellent graft function was maintained for more than 200 days in animals treated with piceatannol + CsA despite cessation of immunosuppression at day 60, indicating that such combination leads to graft acceptance without continuous immunosuppression. We want to examine whether piceatannol is useful for preventing graft rejection in a preclinical non-human primate transplant model. We will: 1) Determine the dose of piceatannol tolerated by rhesus monkeys; and 2) Examine whether piceatannol alone or in combination with subtherapeutic CsA prevents graft rejection in rhesus monkeys. Because the rhesus monkey model has biologic similarity to human renal transplantation, data from this proposal would be critical for future studies with piceatannol in humans.