The involvement of activated T cells and growth-factor production in the early and late phase of chronic kidney allograft nephropathy in rats.
T cells are thought to play a regulatory role in chronic allograft nephropathy (CAN). Thus, we investigated whether lymphocyte inhibition influences CAN. Fisher rat (F-344) kidneys were transplanted orthotopically into Lewis rats. Animals received cyclosporin A (1.5 mg/kg per day, s.c.) for 10 days and were treated daily with either cyclosporin A (1.5 mg/kg), tacrolimus (0.16 mg/kg), or a vehicle thereafter ( n=15 per group). Kidneys were harvested at 16 or 24 weeks. Interleukin-2 (IL-2) and interleukin-2 receptor beta (IL-2Rbeta) mRNA synthesis were intense at 16 weeks and decreased thereafter. Unsurprisingly, both cyclosporin A and tacrolimus significantly inhibited IL-2 and IL-2Rbeta at both time points. Proteinuria increased more rapidly in controls than in treated animals. Morphologically, over 40% of glomeruli were sclerosed by 16 weeks in controls, and ED-1+ macrophages and CD5+ T cells infiltrated the graft. IL-2 mRNA synthesis paralleled the number of infiltrating cells. Inhibition of T-cell proliferation significantly reduced glomerulosclerosis and leukocyte infiltration at both time points. Transforming growth factor (TGF)-beta(1) and platelet-derived growth factor (PDGF) synthesis were highly upregulated in controls at 16 weeks, the time of peak infiltration. At 24 weeks, as cellular infiltration was replaced by scar formation, TGF-beta(1) mRNA returned to normal, while PDGF did not. Inhibition of T cells prevented the upregulation of TGF-beta(1) at both time points; however, PDGF was suppressed only at week 16. These results indicate a beneficial effect of continuous suppression of T cells in CAN. T cells are probably more important in the early, inflammatory phase.
Hamar
Péter
P
Department of Nephrology, University Hospital of Essen, Germany. hampet@net.sote.hu
Szabó
Attila
A
Müller
Veronika
V
Heemann
Uwe
U
D000818:Animals; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology; D006133:Growth Substances / Q000096:biosynthesis*; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology* / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D006133:Growth Substances; D003404:Creatinine