UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Groups of female MRL/MpJ-lpr/lpr mice received either saline or FK506 (tacrolimus; 2 mg/kg intraperitoneally) three times weekly, cyclophosphamide (CY; 20 mg/kg) once monthly, or both drugs from 8 weeks of age. Median survival for untreated and CY-treated mice was 26 weeks, and for FK506- and FK506 + CY-treated groups was > or = 44 weeks. Severity of skin lesions and lymph node hyperplasia was markedly reduced by the drug combination, whereas either drug alone was less effective. FK506 or CY alone delayed the onset of proteinuria, but by 24 weeks all of these animals were positive. In contrast, drug combination reduced the prevalence of proteinuria to < or = 60% throughout the 44 weeks of study. Sequential monitoring of peripheral blood lymphocytes revealed that combination therapy but not monotherapy markedly reduced the proportion of atypical CD3+ B220+ and CD3+CD4-CD8- T cells. Neither FK506 nor CY affected the reduction in IL-2 and IL-4 mRNA levels observed in lymph nodes of diseased animals compared with normals. Although the drug combination also did not affect IL-2 mRNA levels, IL-4 mRNA transcripts were increased six-fold compared with saline-treated controls. IL-10 and interferon-gamma (IFN-gamma) mRNAs were induced by FK506, CY and by the drug combination. Serum levels of anti-dsDNA antibodies were reduced in all treatment groups. These data demonstrate improved efficacy of combined T and B cell-directed immunosuppression in murine lupus, associated with marked inhibition of atypical T cells and selective augmentation of IL-4 within the affected lymphoid tissue.
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PMID:Combined effects of FK506 (tacrolimus) and cyclophosphamide on atypical B220+ T cells, cytokine gene expression and disease activity in MRL/MpJ-lpr/lpr mice. 753 8

Thymopentin (TP-5) is a synthetic pentapeptide that corresponds to the active 32-36 amino acid sequence of the thymic hormone thymopoietin, of which it retains all the immunomodulatory properties. In this study, we have evaluated the effects of long term prophylactic treatment with TP-5 on the clinical, immunological and histological parameters of the SLE-like syndrome that spontaneously occurs in MRL/lpr-lpr (MRL-lpr) mice. TP-5, administered (s.c.) to these mice at the doses of 1, 10 and 100 mg/kg, was given daily, five times a week, from the 9th to the 26th weeks of life. The prophylactic treatment with TP-5 prolonged in a clear dose-dependent fashion the lifespan of MRL-lpr mice as compared with PBS-treated control mice, and the effect reached statistical significance at the doses of 10 and 100 mg/kg. In parallel ex vivo studies, this clinical effect was associated with multiple profound modifications of the immune system including: (i) the reduction of the spontaneous and Con A-induced release of interleukin-4 (IL-4); (ii) the increased secretion of interferon-gamma (IFN-gamma) and IL-6 upon polyclonal mitogenic stimulation, and (iii) the amelioration of the defective Con A-induced lymphoproliferative response. In contrast, although the drug diminished the severity of proteinuria in MRL-lpr mice, it neither reduced histological signs of lupus nephritis nor diminished the serum titres of anti-native DNA and anti-histone autoantibodies. These results indicate that TP-5 displayed powerful immunodulatory activities in a well known model of human SLE.
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PMID:The effects of thymopentin on the development of SLE-like syndrome in the MRL/lpr-lpr mouse. 797 60

As has been reported previously, models of chronic graft-versus-host (GvH) and systemic lupus erythematosus (SLE)-like diseases are characterized by high IgE and IgG1 immunoglobulin (Ig) levels in the serum. An IL-4 induced pathological expansion of Th2 helper cells has been described for both disease models. Due to the immunopharmacological profile of soluble recombinant interleukin-4 receptor (IL-4-R) to bind specifically the corresponding ligand IL-4 and thereby to modulate biological activity upon exogenous administration in various autoimmune disease models, we investigated the immunoregulatory activity of IL-4-R and anti-IL-4 monoclonal antibody (MAb) 11B11 on the development of SLE-like disease in MRL/lpr autoimmune mice and on chronic GvH reaction in BDF1 hybrid mice. Sensitized GvH-BDF1 hybrid mice and SLE in MRL/lpr autoimmune mice were treated in vivo with the IL-4 antagonists to alter the pattern of serum Ig production and to modulate the disease process. These animals were followed for proteinuria, autoantibody production (anti-dsDNA), serum IgE, IgG1 and IgG2a levels, and the survival was monitored. Treatment of these diseased animals resulted in an improved survival rate, lowered the percentage of animals with lymphadenopathy and hepatosplenomegaly, reduced the levels of autoantibodies and inhibited proteinuria of the developing glomerulonephritis in both mouse strains, even in the established diseases. In both models the increase in total IgE and IgG1 levels in serum was strongly inhibited by the IL-4 antagonists, even under therapeutic conditions. But there was no inhibitory activity observed on the IgG2a serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of the immunoglobulin dysregulation in GvH- and SLE-like diseases by the murine IL-4 receptor (IL-4-R). 854 94

To identify the immunologic mechanisms that influence susceptibility to GN, we compared the severity of accelerated anti-glomerular basement membrane (GBM) nephritis between Lewis (LEW) and Brown Norway (BN) rats and analyzed differences in their immune responses to the nephritogenic immunoglobulin. Lewis (LEW) rats preimmunized with sheep IgG developed proliferative GN with marked proteinuria [peak protein excretion (mean +/- SEM) = 85.3 +/- 15.3 mg/24 hr; normal = 6.4 +/- 0.8 mg/24 hr] after receiving a subnephritogenic dose of sheep anti-rat GBM antiserum. Identically treated Brown Norway (BN) rats, on the other hand, had minimal renal pathology and minimal proteinuria (peak protein excretion = 22.6 +/- 3.1 mg/24 hr; normal = 13.0 +/- 0.6 mg/24 hr). Serum titers of rat anti-sheep IgG isotypes and intraglomerular binding of sheep IgG, rat IgG, and rat complement (C3) were comparable in both strains. In contrast, only LEW rats developed a strong cellular immune response to sheep IgG represented by intrarenal T lymphocyte (OX19+) and monocyte (ED1+) accumulation [LEW vs. BN (mean +/- SEM): OX19+ = 0.60 +/- 0.10 vs. 0.14 +/- 0.01 cells/glomerulus, control = 0.02 +/- 0.01; ED1+ = 4.0 +/- 0.4 vs. 1.0 +/- 0.2 cells/glom., control = 0.8 +/- 0.3] and a significant cutaneous delayed-type hypersensitivity (DTH) reaction [LEW versus BN (mean +/- SEM): delta ear thickness = 0.22 +/- 0.02 vs. 0.05 +/- 0.03 mm; control = 0.04 +/- 0.02 mm]. Upon rechallenge with sheep IgG in vitro, LEW splenocytes expressed a T helper 1 (Th1) cytokine pattern (IFN gamma and IL-2 mRNA, but little IL-4 mRNA) which is associated with delayed-type hypersensitivity reactions. BN splenocytes, on the other hand, expressed IL-4 in addition to IL-2 and IFN gamma mRNA that is consistent with an undifferentiated (Th0) cytokine profile. These studies suggest that humoral immunity to heterologous immunoglobulin planted in the kidney is not sufficient for full expression of accelerated anti-GBM nephritis, and that additional cellular immune mechanisms are required. We conclude that susceptibility to accelerated anti-GBM nephritis is strongly influenced by the host's propensity to mount a Th1-type response and DTH reaction to the disease-inciting immunoglobulin.
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PMID:Immunologic determinants of susceptibility to experimental glomerulonephritis: role of cellular immunity. 906 95

The effect of mycophenolate mofetil (MMF) was examined in active Heymann nephritis (HN), an animal model of human membranous nephropathy. HN was induced in Lewis rats with Fx1A/complete Freund's adjuvant (CFA), and controls only received CFA. The induction of HN was prevented by MMF (30 mg/kg per d) from 0 to 4 wk after immunization. Proteinuria was not different in CFA controls up to 16 wk, and was significantly less than in untreated HN from 6 wk onward. Serum anti-Fx1A antibody (Ab) levels and glomerular Ig deposition were suppressed during therapy. The interstitial infiltrate of alphabetaTCR+, CD4+ and CD8+ T cells, natural killer cells, and macrophages (mphi) observed in untreated HN at 8 wk was absent from rats treated from 0 to 4 wk with MMF. Semiquantitative reverse transcription-PCR for renal mononuclear cell cytokine mRNA at 8 wk demonstrated that MMF from 0 to 4 wk prevented the increased expression of Th1 (interferon-gamma, lymphotoxin), Th2 (interleukin-4), and mphi (tumor necrosis factor-alpha) cytokines identified in untreated HN. In lymph node draining sites of immunization, MMF limited both enlargement and the increased proportion of CD3+, CD4+, and CD8+ T cells observed in untreated HN and CFA controls. MMF suppressed Th2 (interleukin-4) but not Th1 (interferon-gamma, lymphotoxin) cytokine mRNA expression in lymph nodes. MMF from 4 to 8, 6 to 12, or 10 to 14 wk did not prevent proteinuria, serum anti-Fx1A Ab, or glomerular IgG deposition when compared with untreated HN. This study showed that MMF from 0 to 4 wk prevented the induction of HN and was associated with preferential suppression of Th2 cytokines. This therapy may prove useful in human idiopathic membranous nephropathy.
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PMID:Mycophenolate mofetil prevents the induction of active Heymann nephritis: association with Th2 cytokine inhibition. 984 81

Idiopathic nephrotic syndrome of childhood is thought to be associated with T lymphocyte dysfunction often triggered by viral infections, with the production of circulating factor(s) resulting in proteinuria. In view of the conflicting evidence of T cell activation and Th1 or Th2 pattern of cytokine synthesis in this disease, this study examined the mRNA expression of interleukin-2 (IL-2), interferon-gamma, IL-4, and IL-13 from CD4+ and CD8+ T cells in steroid-responsive nephrotic patients in relapse and remission. Fifty-five children with steroid-responsive nephrotic syndrome were included in this study, together with 34 normal controls and 24 patient controls with viral infections. RNA was isolated from purified CD4+ or CD8+ cells from peripheral blood and subjected to reverse transcription-PCR. Cytokine mRNA expression was measured semiquantitatively, and a cytokine index was derived from densitometric readings, with cyclophilin as the housekeeping gene. Both cross-sectional and paired data showed an increased CD4+ and CD8+ IL-13 mRNA expression in patients with nephrotic relapse as compared to remission, normal, and patient controls (P < 0.008). This was also associated with increased cytoplasmic IL-13 expression in phorbol myristate acetate/ionomycin-activated CD3+ cells (6.66+/-3.39%) from patients with nephrotic relapse compared to remission (2.59+/-1.35%) (P < 0.0001). However, there was no significant difference in CD4+ or CD8+ IL-2, interferon-gamma and IL-4 mRNA expression. IL-13 is an important T cell cytokine with anti-inflammatory and immunomodulatory functions on B cells and monocytes. It is conceivable that IL-13 may act on monocytes to produce vascular permeability factor(s) involved in the pathogenesis of proteinuria in patients with relapse nephrotic syndrome.
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PMID:Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. 1007 3

The role of IL-4, a key Th2 cytokine, in promoting or inhibiting active Heymann nephritis (HN) was examined. HN is induced by immunization with Fx1A in CFA, and proteinuria in HN is associated with subepithelial IgG and C3 deposition and infiltration of CD8(+) T-cytotoxic 1 (Tc1) cells and macrophages into glomeruli, as well as induction of Abs to Crry. Treatment with rIL-4 from the time of Fx1A/CFA immunization stimulated an earlier IgG1 response to Fx1A, induced anti-Crry Abs, and up-regulated IL-4 mRNA in lymphoid tissue, but did not alter proteinuria. Treatment with MRCOx-81, an IL-4-blocking mAb, resulted in greater proteinuria, which suggests endogenous IL-4 regulated the autoimmune response. Delay of rIL-4 treatment until 4 wk post-Fx1A/CFA immunization and just before the onset of proteinuria prevented the development of proteinuria and reduced Tc1 cell infiltrate in glomeruli. Delayed treatment with IL-4 had no effect on titer or isotype of Abs to Fx1A or on Ig, C3, and C9 accumulation in glomeruli. Treatment with rIL-13, a cytokine that alters macrophage function such as rIL-4, but has no direct effect on T or B cell function, reduced glomerular macrophage infiltrate, but did not prevent proteinuria or CD8+ T cell infiltrate. Anti-Crry Abs were paradoxically only induced with rIL-4 therapy, not in HN controls with proteinuria. It was concluded that the rIL-4 effect was probably by inhibition of Tc1 cells, which normally mediate the glomerular injury that results in proteinuria.
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PMID:Il-4 therapy prevents the development of proteinuria in active Heymann nephritis by inhibition of Tc1 cells. 1156 88

Blockade of angiotensin (Ang) II is efficient in various renal diseases. Although interest has focused on the hemodynamic changes and reduction of proteinuria, recent studies emphasize the nonhemodynamic effects of Ang II on kidney injury. The aim of this study was to clarify the mechanisms of Ang II on the immune system that alter the balance of helper T-cell (Th) subsets. We used a continuous, Ang II infusion model of rats that develop hypertension, proteinuria, and tubulointerstitial damage, including de novo expression of alpha-smooth muscle actin and loss of endothelial cells. We isolated T cells from the spleen and measured cytokine levels by ELISA systems. Ang II-infused rats showed an increase in the Th1 cytokine gamma-interferon and a decrease in the Th2 cytokine interleukin-4. The same change in cytokine mRNA expression in the spleen and kidney was confirmed by quantitative polymerase chain reaction analysis. Our ELISPOT assay showed an increase in the number of gamma-interferon-secreting T cells by Ang II. To investigate whether these changes were specific effects of Ang II, we treated the model rats with the Ang II receptor blocker (ARB) olmesartan or the nonspecific vessel dilator hydralazine. Administration of the ARB ameliorated disease manifestations and the imbalance in Th subsets, whereas hydralazine did not, despite comparable effects on blood pressure. These results demonstrate a direct role of Ang II in the modification of Th balance. The imbalance of Th subsets was associated with hypertensive kidney injury induced by Ang II. Some of the beneficial effects of ARBs might be explained by their immunomodulatory reactions.
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PMID:Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury. 1277 Oct 47

Chronic graft-versus-host disease (GVHD) induced in (C57BL/6 x DBA/2) F1 (BDF1) mice by the injection of DBA/2 mouse spleen cells represents histopathological changes associated with systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and Sjogren's syndrome (SS), as indicated by glomerulonephritis, lymphocyte infiltration into the periportal area of the liver and salivary glands. We determined the therapeutic effect of hepatocyte growth factor (HGF) gene transfection on lupus using this chronic GVHD model. Chronic GVHD mice were injected in the gluteal muscle with either HVJ liposomes containing 8 microg of the human HGF expression vector (HGF-HVJ liposomes) or mock vector (untreated control). Gene transfer was repeated at 2-week intervals during 12 weeks. HGF gene transfection effectively prevented the proteinuria and histopathological changes associated with glomerulonephritis. While liver and salivary gland sections from untreated GVHD mice showed prominent PBC- and SS-like changes, HGF gene transfection reduced these histopathological changes. HGF gene transfection greatly reduced the number of splenic B cells, host B cell major histocompatibility complex class II expression, and serum levels of IgG and anti-DNA antibodies. IL-4 mRNA expression in the spleen, liver, and kidneys was significantly decreased by HGF gene transfection. CD28 expression on DBA/2 CD4+ T cells was decreased by the addition of recombinant HGF in vitro. Furthermore, IL-4 production by DBA/2 CD4+ T cells stimulated by irradiated BDF1 dendritic cells was significantly inhibited by the addition of recombinant HGF in vitro. These results suggest that HGF gene transfection inhibited T helper 2 immune responses and reduced lupus nephritis, autoimmune sialoadenitis, and cholangitis in chronic GVHD mice. HGF may represent a novel strategy for the treatment of SLE, SS and PBC.
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PMID:Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease. 1685 27

The immunosuppressive effects of Sophorae radix (SR) make this plant an attractive agent for the treatment of autoimmune diseases. The effect of SR on systemic lupus erythematosus (SLE) in the New Zealand Black/White F(1) (NZB/w F(1)) mouse model system was investigated. Three-month-old NZB/w F(1) mice were separated into two groups: one treated with SR (1% SR solution by oral administration, daily for 15 weeks) and one with water as a control. Experimental parameters include proteinuria, anti-dsDNA antibody titers, T-cell response and renal histopathological analysis. Results in the SR-treated group showed a significant reduction in proteinuria and anti-dsDNA antibodies either in serum or in glomerular capillaries, along with significant recovery from renal glomerular damage. The lymphocyte population was significantly increased in the SR-treated mice compared with the control group. In the T helper (Th)1/Th2 cytokine secretion profile, interferon-gamma in splenocyte culture was significantly reduced in the SR-treated mice, while interleukin-4 secretion was not altered. These results strongly suggest SR therapy corrects the deviated Th1/Th2 balance, thereby alleviating SLE-like symptoms in the NZB/w F(1) mice. Therefore, SR may be useful in the clinical treatment of SLE.
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PMID:Sophorae radix reduces autoimmune response in NZB/w F1 systemic lupus erythematosus mouse model. 1757 35

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