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      Effects of Interleukin-15 on Vascular Permeability Factor Release by Peripheral Blood Mononuclear Cells in Normal Subjects and in Patients with Minimal-Change Nephrotic Syndrome

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          The characteristic function of interleukin (IL)-15 appears to be its ability to mimic the stimulatory action of IL-2 on lymphocytes by utilizing part of the IL-2 receptor complex. To gain insight into the immunoregulatory properties of this cytokine in patients with minimal-change nephrotic syndrome (MCNS), we analyzed effects of IL-15 on vascular permeability factor (VPF) release in vitro. Peripheral blood mononuclear cells (PBMC) were isolated from 16 patients with MCNS, 16 patients with IgA nephropathy (IgAN) and 16 healthy controls. Cells were stimulated with concanavalin A (Con A) and the VPF was assessed using the method of Lagrue with minor modifications. PBMC secreted significantly increased amounts of VPF under stimulation with Con A in patients with MCNS and IgAN patients with the nephrotic syndrome as compared with normal controls. Here we have demonstrated, for the first time, that addition of IL-15 to PBMC obtained from nephrotic patients as well as from normal controls increased Con A-induced release of VPF by 250%. This stimulatory effect was found highly significant and was dose-dependent. The effect of IL-15 on the secretion of VPF was specific, since a complete reversion was obtained with a neutralizing antibody to human IL-15. Our findings reveal that IL-15 has the potential to function as an immunoregulatory molecule of PBMC VPF release. In addition, IL-15 had similar effects to IL-2 in terms of its capacity to upregulate VPF release. Taken together, our data emphasize a positive regulatory role for IL-15 in inducing the release of VPF when present at optimal levels. Therefore, IL-15 antagonists may provide a basis for immune intervention in the pathophysiology of VPF.

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          Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor

          Interleukin 15 (IL-15) is a novel cytokine that has recently been cloned and expressed. Whereas it has no sequence homology with IL-2, IL- 15 interacts with components of the IL-2 receptor (IL-2R). In the present study we performed a functional analysis of recombinant IL-15 on phenotypically and functionally distinct populations of highly purified human natural killer (NK) cells. The CD56bright subset of human NK cells constitutively expresses the high affinity IL-2R and exhibits a brisk proliferative response after the binding of picomolar amounts of IL-2. Using a proliferation assay, IL-15 demonstrated a very steep dose-response curve that was distinct from the dose-response curve for IL-2. The proliferative effects of IL-15 could be abrogated by anti-IL-2R beta (p75), but not by anti-IL-2R alpha (p55). The proliferative effects of IL-2 on CD56bright NK cells could be inhibited by both antibodies. CD56dim NK cells express the intermediate affinity IL-2R in the absence of the high affinity IL-2R. Activation of CD56dim NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytotoxic activity, antibody-dependent cellular cytotoxicity, and NK cell production of interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cytotoxic activity could be completely blocked by anti-IL-2R beta monoclonal antibody. The binding of radiolabeled IL-2 and IL-15 to CD56dim NK cells was inhibited in the presence of anti-IL-2R beta. Scatchard analysis of radiolabeled IL-15 and IL-2 binding to NK- enriched human lymphocytes revealed the presence of high and intermediate affinity receptors for both ligands. IL-15 is a ligand that activates human NK cells through components of the IL-2R in a pattern that is similar but not identical to that of IL-2. Unlike IL-2, IL-15 is produced by activated monocytes/macrophages. The discovery of IL-15 may increase our understanding of how monocytes/macrophages participate in the regulation of NK cell function.
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            Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis.

            Heavy proteinuria and progressive renal injury recur after transplantation in up to 40 percent of patients with renal failure caused by idiopathic focal segmental glomerulosclerosis. A circulating factor may be responsible for this recurrence. To determine whether patients with focal segmental glomerulosclerosis have a circulating factor capable of causing glomerular injury, we tested serum samples from 100 patients with the disorder in an in vitro assay of glomerular permeability to albumin. Of the 56 patients who had undergone renal transplantation, 33 had recurrences. Sixty-four patients, many of whom had undergone transplantation, were being treated with dialysis. Thirty-one patients with other renal diseases and nine normal subjects were also studied. The 33 patients with recurrent focal segmental glomerulosclerosis after transplantation had a higher mean (+/-SE) value for permeability to albumin (0.47+/-0.06) than the normal subjects (0.06+/-0.07) or the patients who did not have recurrences (0.14+/-0.06). After plasmapheresis in six patients with recurrences, the permeability was reduced (from 0.79+/-0.06 to 0.10+/-0.05, P = 0.008), and proteinuria was significantly decreased. Patients with corticosteroid-sensitive nephrotic syndrome or with membranous nephropathy after transplantation had low levels of serum activity. The circulating factor bound to protein A and hydrophobic-interaction columns and had an apparent molecular mass of about 50 kd. A circulating factor found in some patients with focal segmental glomerulosclerosis is associated with recurrent disease after renal transplantation and may be responsible for initiating the renal injury.
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              Interleukin 12 Upregulates the Release of Vascular Permeability Factor by Peripheral Blood Mononuclear Cells from Patients with Lipoid Nephrosis

              The vascular permeability factor (VPF) is a lymphokine that has been shown to play a role in lipoid nephrosis (LN). Prior studies have shown that interleukin (IL) 12 promotes T helper type 1 differentiation and enhances production of T helper type 1 cytokines such as gamma interferon and IL-2. We, therefore, investigated the effects of recombinant human IL-12 on the release of VPF by peripheral blood mononuclear cells (PBMC) from LN patients. The VPF activity was measured according to the method of Ovary, with minor modifications. The goal of the present study was to examine the importance of IL-12 in concanavalin A induced VPF release in vitro. The levels of VPF were measured in a group of healthy subjects, LN patients with or without the nephrotic syndrome, and patients suffering from IgA nephropathy. There was a significantly increased concanavalin A induced release of VPF in LN and IgA nephropathy patients with nephrotic syndrome as compared with normal controls. Recombinant human IL-12 was found to enhance VPF release in a dose-dependent manner. Neutralization of endogenously produced IL-12 by anti-IL-12 antibody resulted in a decreased release of VPF by LN PBMC. These data indicate that endogenously produced IL-12 functions as a costimulatory molecule in vitro. Our data show that IL-12 can upregulate the release of VPF derived from LN PBMC. Thus IL-12 might be a potent adjuvant for inducing VPF. Therefore, IL-12 antagonists may interfere with newly initiated and ongoing VPF release associated with nephrotic syndrome.

                Author and article information

                S. Karger AG
                May 1999
                28 April 1999
                : 82
                : 1
                : 32-38
                Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
                45365 Nephron 1999;82:32–38
                © 1999 S. Karger AG, Basel

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                Figures: 4, Tables: 1, References: 16, Pages: 7
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