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

Hamar, Péter and Szabó, Attila József and Müller, Veronika and Heemann, Uwe (2002) The involvement of activated T cells and growth-factor production in the early and late phase of chronic kidney allograft nephropathy in rats. Transplant international : official journal of the European Society for Organ Transplantation, 15 (9-10). pp. 446-54. ISSN 0934-0874

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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 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.

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