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)

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 microg/kg rhDNase (n = 8); (2) 125 microg/kg rhDNase (n=6); or (3) placebo (n = 3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre- and post-treatment were studied for immune complex deposition by immunofluorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-alpha) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 microg/kg, but not after SC administration at either dose. A t 1/2 of 3-4h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre- and post-treatment] for the 25 microg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 microg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-alpha. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre- and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.
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PMID:Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. 1002 1

Malaria infections often cause glomerulonephritis (GN), and multiple factors have been implicated in the pathogenesis of glomerular injury. The role of cytokines in malaria associated glomerulonephritis has not been clearly defined. To study the importance of cytokines in malarial nephritis, we investigated the expression of tumour necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), IL-6, IL-10 and granulocyte macrophage-colony stimulating factor (GM-CSF) in kidneys acutely infected with murine malaria parasite Plasmodium berghei ANKA in C57BL/6 J mice. Groups of six mice sacrificed on days 5, 8-10, 15, and 20 postinfection, and normal controls were used for cytokine analysis. Elevated levels of messenger RNA (mRNA) specific for these cytokines in infected kidneys after day 5 postinfection were demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Kidney sections stained with specific antibodies against TNF-alpha, IL-1alpha, IL-6, IL-10 and GM-CSF by immunohistochemistry showed that the staining for these cytokines on the glomeruli was positive from day 10 postinfection, and increased progressively, mainly in the infiltrating macrophages and the glomerular mesangium. Strong correlation was found between the expression of TNF-alpha with IL-6, and IL-1alpha with IL-6. The expression of TNF-alpha, IL-1alpha, IL-6, and IL-10 also strongly correlated with the severity of proteinuria. Our findings show that there is up-regulation of cytokines in the pathogenesis of glomerulonephritis associated with murine malaria infection.
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PMID:Up-regulation of cytokines in glomerulonephritis associated with murine malaria infection. 1046 63

To further elucidate the role of dietary frying oil in the pathogenesis of autoimmune diseases, two groups of NZB/W F1 mice were fed with diets containing 20% fresh oil and frying oil, respectively. All these mice were followed up serum anit-DNA antibody levels, proteinuria and life span regularly. Our data suggested: 1) higher IgG anti-ss, dDNA antibody levels were noted in mice fed with fresh oil compared to those of the frying oil group; 2) lipopolysaccharide (LPS)-stimulated spleen cells of mice fed with frying oil produced higher IL-10 compared to that of fresh oil group; 3) IL-6, TNF-alpha and PGE2 produced by macrophages of dietary frying oil group were higher, although not statistically significant, than those of fresh oil group. Different degree of deterioration of dietary oil has been found to affect immune response in autoimmune mice.
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PMID:Dietary frying oil influences immune regulation in autoimmune-prone NZBxNZW F1 mice. 1059 94

Peptides based on the complementarity-determining region 1 (CDR1) and CDR3 of an anti-DNA monoclonal antibody (mAb) carrying the 16/6 idiotype (Id) were shown to induce experimental systemic lupus erythematosus (SLE) in susceptible mouse strains. In the present study, T-cell lines specific to the pCDR1 and pCDR3 peptides were established in BALB/c and in SJL mice, respectively. The T-cell lines were characterized and analysed for their pathogenicity upon administration to syngeneic mouse strains. Both T-cell lines expressed the alphabeta T-cell receptor (TCR) and the CD4+ CD8- phenotype. Additionally, both cell lines secreted interleukin (IL)-4 and IL-10 upon stimulation with their specific peptide, thus belonged to the T helper 2 (Th2) subset. Upon immunization, the pCDR3-specific T-cell line induced experimental SLE in SJL mice. The animals produced high levels of autoimmune anti-DNA and antinuclear protein antibodies, as well as anti-16/6 Id antibodies (Abs). Furthermore, the mice developed clinical manifestations, including leukopenia, proteinuria and accumulation of immune complex deposits in their kidneys. The pCDR1-specific T-cell line failed to induce SLE when injected into BALB/c mice. It is thus suggested that pCDR3 is an immunodominant epitope in experimental SLE and that pCDR3-specific T cells initiate autoimmunity, leading to SLE, probably via epitope spreading.
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PMID:Characterization and role in experimental systemic lupus erythematosus of T-cell lines specific to peptides based on complementarity-determining region-1 and complementarity-determining region-3 of a pathogenic anti-DNA monoclonal antibody. 1069 45

Previous study suggested that MRL-lpr/lpr mice treated with tamoxifen (TAM) had less severe proteinuria, reduced serum titre of anti-dsDNA autoantibodies and an increased survival rate. To investigate further the regulatory mechanisms of TAM on MRL-lpr/lpr female mice, a total dose of 200 microg per mice (5.5 mg/kg) was given every 2 weeks subcutaneously, while the control mice were injected with oil only. After being treated with TAM four times, the mice were killed and cellular functions were evaluated. The TAM-treated groups had smaller sized spleen and lymph nodes. Flow cytometric analysis of splenocytes had a significantly lower percentage of cell number of T cells and double negative T cells (CD4- CD8- T cells). There was no difference in cytokine production (interleukin (IL)-2, IL-4, IL-5, IL-10 and interferon-gamma (IFN-gamma)) from splenocytes stimulated with concanavalin A (Con A) or cytokines (IL-6) secreted by peritoneal exudate cells when stimulated with lipopolysaccharide (LPS). However, IL-2 from lymph node cells was significantly higher on TAM-treated mice. Finally, splenocytes or purified T cells stimulated with anti-CD3 antibody plus cross-linking immunoglobulin G (IgG) of the TAM-treated group had higher 3H-incorporation of proliferation assay compared with that of control groups. In vitro study further demonstrated that IL-2-activated proliferation of lymph node double negative (DN) T cells can be inhibited by TAM treatment in a dose-dependent manner. Our finding demonstrated that TAM may potentially influence T cells and modulate the immune function, which offers a novel approach to explore the feasibility of hormone therapy for autoimmune diseases.
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PMID:Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune MRL-lpr/lpr mice. 1080 66

The contribution of B7.1 and B7.2 co-stimulation to Th1-directed, cell-mediated renal injury was studied in a murine model of crescentic glomerulonephritis (GN) initiated by a "planted" antigen. Mice treated with anti-B7.2 monoclonal antibody (mAb), starting prior to disease initiation, developed more severe renal injury with increased glomerular crescent formation (p = 0.031), glomerular accumulation of T cells (p = 0.014) and proteinuria (p = 0.022) compared to mice treated with control antibodies. Mice treated with anti-B7.1 mAb had reduced crescent formation (p = 0.019) compared to control treated mice, but reductions in glomerular CD4(+) T cell accumulation and proteinuria were not statistically significant. B7. 1 mAb treatment significantly reduced all parameters of renal injury (above) compared to anti-B7.2 mAb treatment. Neither treatment altered the circulating antibody titer or cutaneous delayed type hypersensitivity to the nephritogenic antigen. Antibody subclasses and antigen-stimulated ex vivo splenocyte IL-4, IL-10 and IFN-gamma production did not indicate effects on Th subset responses. Treatment with CTLA4-Fc or combined treatment with anti-B7.1 and B7. 2 antibodies did not significantly attenuate crescentic GN. These data indicate that B7.1 and B7.2 are important co-stimulatory molecules involved in crescentic GN, which have opposing effects on disease development without altering the T helper cell subset response to the nephritogenic antigen.
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PMID:B7.1 and B7.2 co-stimulatory molecules regulate crescentic glomerulonephritis. 1082 Mar 86

In a previous experiment we demonstrated the induction of tolerance by the allograft itself. In this model of weak histoincompatibility, second grafts of donor origin replacing chronically rejected first renal allografts were accepted long term. Additionally grafted donor-specific hearts functioned indefinitely while adoptive transfer experiments demonstrated the development of donor-specific transferable tolerance. In the current experiment we compared intragraft gene expression of chronically rejected first and tolerant second grafts by RT-PCR. Second renal allografts of donor origin (F-344) replaced first grafts 2, 4, 8, 12, and 16 weeks after the initial engraftment. No immunosuppression was used during second engraftment. Grafts were followed by serial proteinuria; morphological and immunohistological studies (APAAP/infiltrating cells, ICAM-1, MHC II expression) and competitive RT-PCR analyses (expressed as arbitary units AU/cDNA) for relevant cells and cytokines (CD-3, IFNgamma, IL-10, and IL-4) were assessed by the end of the observation period (16 weeks). Macrophages/monocytes (ED-1+) and T-cells (CD-5 and CD-4+) infiltrated first allografts in high numbers by 12 weeks associated with strong structural signs of chronic graft rejection (ca. 30% arterio- and glomerulosclerosis, tubular atrophy and interstitial fibrosis). Cellular infiltrates in second grafts were prominent, however significantly reduced, while histological changes were minor. At cDNA levels, CD-3 transcripts were elevated in second renal allografts performed 2, 4, and 8 weeks after the initial engraftment while comparable levels were observed when second engraftment was performed after 12 and 16 weeks. Analyses of relevant cytokines demonstrated a TH1/TH2 shift independent from the time interval between first and second engraftment. These results emphasize the role of alloresponsiveness for the development of chronic graft dysfunction. Mechanisms of tolerance induction in our model are associated with a distinct alloresponsive pattern. A crucial role for regulatory T-cells is suggested.
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PMID:Mechanisms of tolerance induction in second renal allografts of a chronic rejection model. 1111 58

IL-10 displays modulatory properties on the synthesis of platelet-activating factor (PAF), a potent inflammatory mediator of vascular injury. Despite the fact that IL-10 is considered to be an anti-inflammatory cytokine, IL-10 levels correlate with disease activity in SLE. Moreover, in SLE IL-10 is unable to exert its immunosuppressive and anti-inflammatory effects. We have investigated the ability of IL-10 to stimulate PAF production from monocytes of SLE patients. Spontaneous and IL-10-stimulated PAF production by peripheral blood monocytes was measured in active (n = 13) and inactive (n = 14) SLE patients and in 15 normal control subjects. We observed that monocytes derived from patients with active SLE, but not from controls or inactive SLE, spontaneously produced significant amounts of PAF. Moreover, IL-10 enhanced the synthesis of PAF from monocytes of active SLE patients only. IL-10-induced PAF production correlated with the severity of the disease and with the extent of proteinuria. These results indicate that IL-10 only stimulates the synthesis of PAF from monocytes of SLE patients when immunologically active, suggesting that IL-10 may possess a paradoxical proinflammatory effect in SLE by promoting the production of PAF, a secondary mediator of inflammation.
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PMID:IL-10 stimulates production of platelet-activating factor by monocytes of patients with active systemic lupus erythematosus (SLE). 1112 57

Hantaviruses cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Approximately 200,000 cases are reported annually, and there is to date no specific treatment available. A major obstacle in studying the medical aspects of HFRS and HPS has been the lack of an adequate animal model. Here we show that infection of cynomolgus macaques by wild-type Puumala hantavirus resulted in typical signs of HFRS including lethargy, anorexia, proteinuria, and/or hematuria, in addition to cytokine (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha), C-reactive protein, creatinine, and nitric oxide responses. Viral RNA was detected in plasma from days 3 to 7 postinoculation until days 24 to 28 postinoculation, infectious virus was recovered, and the virus-specific immune responses (immunoglobulin M [IgM], IgG, and neutralizing antibodies) mimicked those seen in humans. The results indicated that the monkey model will provide a valuable tool for studies of pathogenesis, candidate vaccines, and antivirals for hantavirus disease.
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PMID:Wild-type Puumala hantavirus infection induces cytokines, C-reactive protein, creatinine, and nitric oxide in cynomolgus macaques. 1173 12

Two peptides based on the complementarity-determining regions (CDR) 1 and 3 (pCDR1 and pCDR3) of a murine monoclonal anti-DNA autoantibody that expresses the common idiotype 16/6Id were shown to down-regulate systemic lupus erythematosus (SLE)-associated T cell responses and to prevent the development of clinical symptoms in the SLE-prone mice, (NZB x NZW)F(1). In the present study the ability of the CDR-based peptides to treat an already established disease was tested. Mice were given 10 weekly injections of peptides either i.v. or s.c. The treatment led to a moderate reduction in the anti-DNA autoantibody titer, and a significant decrease in proteinuria and kidney pathology. The CDR-based peptides affected the pathogenic isotypes (IgG2a and IgG3) of the anti-DNA antibodies in the serum and in immune complexes in the kidneys. Both peptides mitigated disease manifestations and prolonged the survival of mice that were treated starting at the age of 7 months when full-blown disease was already developed. Furthermore, some beneficial effects of treatment with the CDR-based peptides could be adoptively transferred to diseased recipients. A reduction in the secretion of IL-2, IFN-gamma, IL-4 and IL-10 was detected in supernatants of splenocytes of the treated mice. In contrast, treatment up-regulated the immunosuppresive cytokine-transforming growth factor-beta. Thus the ameliorating effect of the CDR-based peptides on SLE manifestations is at least partially via the immunomodulation of the cytokine profile.
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PMID:Peptides based on the complementarity-determining regions of a pathogenic autoantibody mitigate lupus manifestations of (NZB x NZW)F1 mice via active suppression. 1257 50

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