Protective effects of FTY720 on chronic allograft nephropathy by reducing late lymphocytic infiltration.
BACKGROUND
Lymphocytic infiltration is obvious throughout early and late stages of chronic allograft nephropathy. Early infiltrating lymphocytes are involved in initial insults to kidney allografts, but the contribution of late infiltration to long-term allograft attrition is still controversial. Early application of FTY720 reduced the number of graft infiltrating lymphocytes, and inhibited acute rejection. The present study investigated the potential of FTY720 to reduce the number of infiltrating lymphocytes even at a late stage, and, thus, slow the pace of chronic allograft nephropathy.


METHODS
Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients with an initial 10-day course of cyclosporine A (1.5 mg/kg/day). FTY720, at a dose of 0.5 mg/kg/day, or vehicle was administered to recipients either from weeks 12 to 24 or from 20 to 24 after transplantation. Animals were harvested 24 weeks after transplantation for histologic, immunohistologic, and molecular analysis.


RESULTS
FTY720, either initiated at 12 or 20 weeks after transplantation, reduced urinary protein excretion, and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, and intimal proliferation of graft arteries at 24 weeks after transplantation. Furthermore FTY720 markedly suppressed lymphocyte infiltration and decreased mRNA levels of interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and platelet-derived growth factor-B (PDGF-B) but enhanced the number of apoptotic cells in grafts.


CONCLUSIONS
FTY720 ameliorated chronic allograft nephropathy even at advanced stages. Furthermore, our data suggest that this effect was achieved by a reduction of graft infiltrating lymphocytes.
Department of Nephrology TU-Klinikum rechts der Isar, Munich, Germany.
Minghui
M
Wang
Shanying
S
Liu
Nengtai
N
Ouyang
Erwei
E
Song
Jens
J
Lutz
Uwe
U
Heemann
D000818:Animals; D002908:Chronic Disease; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013110:Sphingosine / Q000031:analogs & derivatives; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine