FK778, a powerful new immunosuppressant, effectively reduces functional and histologic changes of chronic rejection in rat renal allografts.
BACKGROUND
FK778 is a new derivative of the active leflunomide metabolite A77 1726. It effectively prevented acute allograft rejection in several experimental transplant models, and it is currently in phase II trials in human transplant recipients. In this study, we examined the effects of FK778 in a well-established model of chronic renal allograft rejection in the rat.


METHODS
Kidneys of Lewis (LEW) and F344 rats were orthotopically transplanted into bilaterally nephrectomized LEW recipients as the isograft and allograft control, respectively. Allograft recipients were orally administered FK778 at doses of 3 mg/kg per day, 10 mg/kg per day, and 20 mg/kg per day for 10 days. Blood and 24-hr urine samples were collected once a week after grafting for plasma creatinine, allo-specific antibodies, and proteinuria determination. Kidney grafts were harvested on the 90th day after transplantation and subjected to histologic, immunohistologic, and reverse transcriptase-polymerase chain reaction analysis. Histologic sections were semiquantitatively scored using criteria adapted from the Banff' classification for transplant pathologic conditions.


RESULTS
Recipients treated with FK778 for 10 days exhibited a dose-dependent decrease in proteinuria and plasma creatinine for the entire 90-day period after transplantation when compared with the allograft control. FK778, at doses of 10 mg/kg per day and 20 mg/kg per day, remarkably reduced chronic histologic changes, including tubular atrophy, glomerulosclerosis, fibrointimal hyperplasia, and transplant glomerulopathy. In addition, FK778 treatment was associated with decreased intragraft mononuclear cell infiltration, serum allo-specific immunoglobulin (Ig)M and IgG antibody production, and intragraft transforming growth factor beta messenger RNA expression in those recipients surviving 90 days after transplantation when compared with the allograft control.


CONCLUSIONS
FK778 effectively reduces functional and histologic chronic kidney allograft rejection in the rat.
Pan
Fan
F
Basic Science, Fujisawa Research Institute of America, Evanston, IL 60201-3135, USA.
Ebbs
Aaron
A
Wynn
Carmen
C
Erickson
Laurie
L
Jang
Mei-Shiang
MS
Crews
Gladys
G
Fisniku
Ogert
O
Kobayashi
Masakazu
M
Paul
Leendert C
LC
Benediktsson
Hallgrimur
H
Jiang
And Hongsi
AH
D000480:Alkynes; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006084:Graft Rejection / Q000473:pathology* / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007518:Isoantibodies / Q000276:immunology; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology; D009570:Nitriles; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D016212:Transforming Growth Factor beta / Q000235:genetics; D014184:Transplantation, Homologous
D000480:Alkynes; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D007555:Isoxazoles; D009570:Nitriles; D016212:Transforming Growth Factor beta; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide