The involvement of activated T cells and growth-factor production in the early and late phase of chronic kidney allograft nephropathy in rats

Abstract.

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 β (IL-2Rβ) mRNA synthesis were intense at 16 weeks and decreased thereafter. Unsurprisingly, both cyclosporin A and tacrolimus significantly inhibited IL-2 and IL-2Rβ 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)-β₁ 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-β₁ mRNA returned to normal, while PDGF did not. Inhibition of T cells prevented the upregulation of TGF-β₁ 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.