title: Piceatannol in combination with low doses of cyclosporine A prolongs kidney allograft survival in a stringent rat transplantation model.
abstract: BACKGROUND
  The discovery of new immunosuppressive agents has enhanced short-term graft survival. However, current immunosuppressants often induce toxicities that limit their clinical use. Thus, there is a need for new immunosuppressants for use in clinical transplantation. Piceatannol blocks Syk and ZAP-70, tyrosine kinases involved in immune cell activation. We examined whether piceatannol prolongs kidney allograft survival in the stringent ACI-to-Lewis rat model.
  
  
  METHODS
  Kidney recipients were divided into four groups. Group 1 (n=8) received piceatannol 30 mg/kg per day intravenously and cyclosporine A (CsA) 2 mg/kg per day intramuscularly from day -3 to day 7 after transplantation. At day 8, piceatannol was reduced to 10 mg/kg per day and the combined treatment continued until day 60. Group 2 (n=9) received 2 mg/kg per day CsA alone from day -3 to day 60. Group 3 (n=4) received piceatannol alone as in group 1. Group 4 (n=2) received only the vehicle dimethyl sulfoxide from day -3 to day 60. Graft rejection was defined as either a serum creatinine level more than 2 mg/dL or animal death.
  
  
  RESULTS
  Group 1 animals survived for at least 115 days (n=8, P<0.05), with several animals maintaining their grafts for more than 200 days. In contrast, 8 of 9 animals in group 2 rejected their grafts within 10 days of transplantation; one animal survived for 71 days. Excellent graft function was maintained in group 1 animals despite withdrawal of immunosuppression.
  
  
  CONCLUSIONS
  These results are the first to show that piceatannol, when combined with subtherapeutic dosages of CsA, prevents graft rejection, suggesting that targeting Syk and Zap could be useful for preventing graft rejection.
authors.affiliation: Department of Surgery, Division of Transplantation, Laboratory of Transplant Immunology, University of Wisconsin-Madison, WI, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Fernandez
authors.forename: Jose
authors.initials: J
authors.lastname: Torrealba
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yagci
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ishido
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuchida
authors.forename: Hyoung
authors.initials: H
authors.lastname: Tae Kim
authors.forename: Yinchen
authors.initials: Y
authors.lastname: Dong
authors.forename: Terry
authors.initials: T
authors.lastname: Oberley
authors.forename: John
authors.initials: J
authors.lastname: Fechner
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Colburn
authors.forename: Jackie
authors.initials: J
authors.lastname: Schultz
authors.forename: Turan
authors.initials: T
authors.lastname: Kanmaz
authors.forename: Huaizhong
authors.initials: H
authors.lastname: Hu
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Knechtle
authors.forename: Majed M
authors.initials: MM
authors.lastname: Hamawy
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation; D007958:Leukocyte Count; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012016:Reference Values; D013234:Stem Cells / Q000473:pathology; D013267:Stilbenes / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology; D013936:Thymidine / Q000493:pharmacokinetics; D014184:Transplantation, Homologous; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D013267:Stilbenes; D014443:Tyrosine; C041525:3,3',4,5'-tetrahydroxystilbene; D016572:Cyclosporine; D013936:Thymidine