Piceatannol in combination with low doses of cyclosporine A prolongs kidney allograft survival in a stringent rat transplantation model.
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.
Fernandez
Luis A
LA
Department of Surgery, Division of Transplantation, Laboratory of Transplant Immunology, University of Wisconsin-Madison, WI, USA.
Torrealba
Jose
J
Yagci
Gökhan
G
Ishido
Nobuhiro
N
Tsuchida
Masahiro
M
Tae Kim
Hyoung
H
Dong
Yinchen
Y
Oberley
Terry
T
Fechner
John
J
Colburn
Matthew J
MJ
Schultz
Jackie
J
Kanmaz
Turan
T
Hu
Huaizhong
H
Knechtle
Stuart J
SJ
Hamawy
Majed M
MM
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
D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D013267:Stilbenes; D014443:Tyrosine; C041525:3,3',4,5'-tetrahydroxystilbene; D016572:Cyclosporine; D013936:Thymidine