Induction of T regulatory cells attenuates idiopathic nephrotic syndrome - PubMed (original) (raw)

Induction of T regulatory cells attenuates idiopathic nephrotic syndrome

Ludmilla Le Berre et al. J Am Soc Nephrol. 2009 Jan.

Abstract

Buffalo/Mna rats spontaneously develop FSGS and nephrotic syndrome as a result of an immune disorder. Similar to some humans with FSGS, the disease recurs after renal transplantation, suggesting the involvement of a circulating factor. Here, we tested the effect of several immunosuppressive treatments on these rats. Although corticosteroids, cyclosporin A, and anti-T cell receptor treatment reduced proteinuria, only the deoxyspergualin derivative LF15-0195 led to a rapid and complete normalization of proteinuria. Furthermore, this compound led to the regression of renal lesions during both the initial disease and posttransplantation recurrence. The frequency of splenic and peripheral CD4+CD25+FoxP3+ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195-induced CD4+CD25+ T cells to irradiated Buff/Mna rats significantly reduced their proteinuria compared with the transfer of untreated control cells, suggesting that LF15-0195 induces regulatory T cells that are able to induce regression of rat nephropathy. These data suggest that idiopathic nephrotic syndrome/FSGS disease can be regulated by cellular transfer, but how this regulation leads to the reorganization of the podocyte cytoskeleton remains to be determined.

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Figures

Figure 1.

Figure 1.

(A) Beneficial effect of a derivative of DSG, LF15-0195, on both the onset of proteinuria and established proteinuria in young Buff/Mna rats. Each treatment was administered for 30 d at a dosage of 1 mg/kg per d (n = 5). The control group consisted of vehicle-treated Buff/Mna rats. (B) Effect of LF15-0195 compared with LF15-0296, an isomer without any immunosuppressive effect, on the proteinuria of 6-mo-old Buff/Mna rats. The two treatments were administered for 30 d (n = 5). (C) LF15-0195 reduced the proteinuria of Buff/Mna rats experiencing recurrence of their initial disease after kidney transplantation. The treatment was administered for 30 d (n = 5). The control group consisted of untreated Buff/Mna rats experiencing recurrence of proteinuria after kidney transplantation (n = 5). Proteinuria is expressed as the ratio of the urinary proteins (g/L) to urinary creatinine concentration (mmol/L). Data are means ± SEM (scale bar). *Significant decrease in proteinuria (versus day 0), P < 0.05; **P < 0.01.

Figure 2.

Figure 2.

(A through D) Light microscopic examination of native kidneys from untreated age-matched Buff/Mna rats showing major tubular alterations (A) and FSGS lesions (C; n = 4) and LF15-0195-treated Buff/Mna kidneys showing a subnormal renal interstitium (B) without glomerulosclerosis (D; n = 6; periodic acid-Schiff staining). (E and F) Electron microscopic examination of age-matched kidneys of native Buff/Mna rats showing some flattening and foot process fusion (E), compared with LF15-0195–treated Buff/Mna kidneys showing a normal ultrastructure with well differentiated and organized foot processes (F). Magnifications: ×100 in A and B; ×200 in C and D; ×15,000 in F.

Figure 3.

Figure 3.

Decrease in renal infiltration of monocytes, T lymphocytes, and associated cytokines upon LF15-0195 treatment. (A and B) Results are expressed as the percentage (means ± SEM) of the surface area occupied by positive cells. Each group consisted of five or six rats. The control groups consisted of age-matched Buff/Mna rats. (A) Monocyte-macrophage (ED1 Ab) populations. (B) T lymphocytes (R7.3 Ab). (C through E) IL-10 (C), IL-13 (D), and TNF-α (E) mRNA expression was analyzed by quantitative RT-PCR in the kidneys of LF15-0195–treated or untreated age-matched Buff/Mna rats. Data are means ± SEM of arbitrary units (AU) relative to HPRT (n = 6). *P < 0.05; **P < 0.01.

Figure 4.

Figure 4.

Significant increase in blood CD4+CD25+ T lymphocytes after LF15-0195 treatment of Buff/Mna rats. (A and B) Representative FACS staining of PBMC of LF15-0195–treated Buff/Mna (A) versus untreated age-matched Buff/Mna rats (B) shows a significant increase in the frequency of CD4+CD25+ T cells (similar dot plots and histograms not shown for splenocytes). (C) Results are expressed as the percentage of CD4+CD25+ T cells in PBMC or splenocytes of untreated or treated Buff/Mna rats at either day 15 or the end (day 30) of the treatment. (A through C) Cells labeled with control isotype antibodies were used as a negative control and are represented in gray on the histogram. (D) Representative histogram of the percentage of FoxP3-positive cells (FoxP3-PE) contained in the CD4+CD25+ T cells as described previously for LF15-0195–treated rats. The dotted line in the histogram represents the percentage of FoxP3+ cells in CD4+CD25+ T cells from untreated rats. *P < 0.05; **P < 0.01.

Figure 5.

Figure 5.

Accumulation of transcripts for the regulatory markers CD25, CTLA4, GITR, IDO, and iNOS in LF15-0195–treated in comparison with untreated age-matched spleens. mRNA expression was analyzed by quantitative RT-PCR. Data are means ± SEM of AU relative to HPRT (n = 6). *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 6.

Figure 6.

Transient regulation of nephropathy after transfer of CD4+CD25+ T cells from Buff/Mna rats in remission into Buff/Mna rats. Purified CD4+CD25+ T cells from LF15-0195–treated Buff/Mna were injected into 4 Gy–irradiated proteinuric Buff/Mna rats (n = 5). The number of injected cells was equivalent in the two groups: 2.57 ± 0.8 × 106 cells in the untreated group and 2.97 ± 0.8 × 106 cells in the LF15-0195 treated group (NS). Data are means ± SEM (scale bar) and are compared with a control group injected with purified cells from untreated rats (n = 5). *P < 0.05, **P < 0.01 between the two experimental groups.

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References

    1. Dantal J, Giral M, Hourmant M, Soulillou JP: Glomerulonephritis recurrences after kidney transplantation. Curr Opin Nephrol Hypertens 4: 146–154, 1995 - PubMed
    1. Artero ML, Sharma R, Savin VJ, Vincenti F: Plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent focal glomerulosclerosis. Am J Kidney Dis 23: 574–581, 1994 - PubMed
    1. Dantal J, Bigot E, Bogers W, Testa A, Kriaa F, Jacques Y, Hurault de Ligny B, Niaudet P, Charpentier B, Soulillou JP: Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 330: 7–14, 1994 - PubMed
    1. Dantal J, Godfrin Y, Koll R, Perretto S, Naulet J, Bouhours JF, Soulillou JP: Antihuman immunoglobulin affinity immunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome. J Am Soc Nephrol 9: 1709–1715, 1998 - PubMed
    1. Oliver JD 3rd, Simons JL, Troy JL, Provoost AP, Brenner BM, Deen WM: Proteinuria and impaired glomerular permselectivity in uninephrectomized fawn-hooded rats. Am J Physiol 267: F917–F25, 1994 - PubMed

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