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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of systemic lupus erythematosus (SLE) presents a significant therapeutic challenge: multi-organ involvement and a variable disease course characterized by clinical exacerbations and remissions make it difficult to predict outcome. Few products have been specifically developed in this clinical indication and most accepted therapies have not been tested in randomized controlled trials in SLE. A variety of biologic agents under investigation as potential treatments for SLE are designed to interfere with specific immunologic responses, hopefully avoiding generalized immunosuppression. These include therapies to downregulate IL-10 and/or upregulate TGFb production. Agents which interfere with T cell activation and T cell-B cell collaboration, such as CTLA4-Ig and anti-CD40 ligand monoclonal antibodies, may result in long term therapeutic benefit; alone or in combination, even following brief treatment courses. Products designed to decrease production of anti-dsDNA antibodies or inhibit complement activation may prevent immune complex deposition and amerliorate organ-specific manifestations such as renal disease. More aggressive interventions include gene therapy and stem cell transplantation. As these agents enter clinical trials, efforts to develop international consensus regarding trial methodology and outcome measures will be crucial to their successful development.
Lupus 2001
PMID:Monoclonal antibodies and other biologic therapies. 1131 56

In systemic lupus erythematosus hyperactive helper T-cells drive polyclonal B-cell activation and secretion of pathogenic auto-antibodies. The auto-antibodies form immune complexes with their respective auto-antigens, which in turn deposit in sites such as the kidney and initiate a destructive inflammatory reaction. Lupus nephritis can be managed successfully in the majority of cases; however, the most widely used immunosuppressive therapies, notably corticosteroids and cyclophosphamide are non-specific and are associated with substantial toxicities. Novel treatments for lupus nephritis have to be at least as effective and less toxic than existing therapies. The ultimate aim is to develop treatments that target specific steps in the disease process. Novel therapeutic strategies in the short-term more likely will focus on refining regimens of drugs that are already in use (mycophenolate mofetil, adenosine analogues) and combinations of existing chemotherapeutic agents, as well as attempts to achieve immunological reconstitution using immunoablative chemotherapy with or without haematopoietic stem cell rescue. Several new agents targeting specific steps in the pathogenesis of lupus are in various phases of clinical development. Interrupting the interactions between T-lymphocytes and other cells by blocking co-stimulatory molecules, such as CD40 ligand or CTLA4-Ig, may interfere with the early steps of pathogenesis. Blocking IL-10 may decrease auto-antibody production and help normalise T-cell function. Treating patients with DNase or interfering with the complement cascade by blocking C5, or neutralising pathogenic antibodies by administering specific binding peptides or inducing specific anti-idiotype antibodies may prevent immune complex formation and/or deposition.
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PMID:Novel approaches in the treatment of lupus nephritis. 1177 39

Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and the production of autoantibodies, some of which (antibodies to dsDNA) are thought to be pathogenic. T helper cells drive the production of autoantibodies and the aim of this study is to characterize phenotypically a subpopulation of T cells (the CD3+ CD4- CD8-, double negative (DN) T cells) previously identified as helping to enhance anti-DNA antibodies in patients with SLE. Data were obtained using FACS staining of DN T cells that had been purified from PBMCs by magnetic bead separation. The percentage of TCR alphabeta+ DN T cells was found to be significantly higher in patients with SLE as compared with controls (P = 0.02), although there was no significant increase in total percentage of DN T cells, which includes TCR gammadelta+ cells. Activation markers HLA-DR and CD69, the costimulatory molecule CD28 and CTLA-4 were all expressed on the surface of a higher percentage of DN T cells in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls (HC). More DN T cells from patients with SLE were of CD45RA phenotype than was found in controls, while CD45RO-expressing cells were reduced. In addition, DN T cells from patients with SLE expressed significantly higher levels of HLA-DR (P = 0.006), CD28 (P = 0.05), CTLA4 (P = 0.03) and CD45RA (P = 0.05) on the cell surface than those from the CD4/8 population. Correlation of expression of the markers measured with various parameters of disease activity and severity showed that high levels of HLA-DR expression correlated with high circulating serum C3 (> 0.9 IU/ml), indicating that an activated phenotype is consistent with severe disease.
Lupus 2002
PMID:Characterization of CD3+ CD4- CD8- (double negative) T cells in patients with systemic lupus erythematosus: activation markers. 1222 Jan 3

Collagen Induced Arthritis (CIA) is a widely studied animal model to develop and test novel therapeutic approaches for treating Rheumatoid Arthritis (RA) in humans. Soluble Cytotoxic T-Lymphocyte Antigen 4 (CTLA4-Ig), which binds B7 molecule on antigen presenting cells and blocks CD28 mediated T-lymphocyte activation, has been shown to ameliorate experimental autoimmune diseases such as lupus, diabetes and CIA. Objective of our research was to investigate in vivo the effectiveness of blocking the B7/CD28 T-lymphocyte co-stimulatory pathway, utilizing a gene transfer technology, as a therapeutic strategy against CIA. Replication-deficient adenoviruses encoding a chimeric CTLA4-Ig fusion protein, or beta-galactosidase as control, have been injected intravenously once at arthritis onset. Disease activity has been monitored by the assessment of clinical score, paw thickness and type II collagen (CII) specific cellular and humoral immune responses for 21 days. The adenovirally delivered CTLA4-Ig fusion protein at a dose of 2x10^8 pfu suppressed established CIA, whereas the control beta-galactosidase did not significantly affect the disease course. CII-specific lymphocyte proliferation, IFNgamma production and anti-CII antibodies were significantly reduced by CTLA4-Ig treatment. Our results demonstrate that blockade of the B7/CD28 co-stimulatory pathway by adenovirus-mediated CTLA4-Ig gene transfer is effective in treating established CIA suggesting its potential in treating RA.
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PMID:[Recombinant adenovirus-mediated gene transfer suppresses experimental arthritis] 1246 78

Systemic lupus erythematosus (SLE) is a CD4(+) T cell-dependent, immune complex-mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb's or CTLA4-Ig and anti-CD154 mAb's have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB x NZW F(1) mice given three injections of anti-CD137 (4-1BB) mAb's between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice's lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB x NZW F(1) mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4(+) T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4(+) T cells during priming at the DC interface.
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PMID:CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. 1275 Apr

The cytotoxic T-lymphocyte antigen 4 (CTLA4, CD152) gene is a positional and functional candidate gene to susceptibility to systemic lupus erythematosus (SLE) because CTLA4 gene maps in the described SLE risk region 2q33 and CTLA4 molecule has an inhibitory effect on T-cell activation. Several polymorphisms have been described in CTLA4 gene, among them, a T/C change at position -1722, a C/T transition at position -319, and another A/G transition at position +49. The aim of this study was to investigate the possible association of these polymorphisms with the susceptibility to SLE in 276 Spanish autochthonous patients using a healthy control group composed of 194 ethnically matched volunteer bone marrow donors. Genotyping of these CTLA4 positions was performed in SLE patients and controls using a polymerase chain reaction amplification refractory mutation system. The genotypic frequencies were in Hardy-Weinberg equilibrium in all patients. No differences in the distribution of the genotype frequencies between patients and controls were found in any case. Our results from the Spanish autochthonous population differ from those found in the Korean population regarding the involvement of the polymorphism located at -1722 in the susceptibility to SLE.
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PMID:CTLA4 polymorphism in Spanish patients with systemic lupus erythematosus. 1452 90

The objective of this study was to determine the expression and activity of CTLA4 in T-cells of systemic lupus erythematosus (SLE) patients. Expression of CTLA4 on freshly isolated peripheral blood T-cells was evaluated in 33 SLE patients and 25 controls using flow cytometry. The T-cells from 19 SLE patients and 22 controls were stimulated and cultured with Chinese hamster ovary cells expressing CD80 (CHO-CD80) or with CHO cells. T-cell proliferation was determined with [3H] thymidine incorporation (CPM), and the inhibitory effect of CTLA4 on T-cell proliferation was evaluated by the ratio of CPM for T-cells with CHO-CD80 cells to that of T-cells with CHO cells (the CHO-CD80/CHO ratio). Intracellular CTLA4 expression in freshly isolated peripheral blood T-cells was significantly higher in SLE patients than the controls (P < 0.05), but there was no correlation with clinical features or disease activity. The CHO-CD80/CHO ratio of SLE patients was significantly higher than that of the controls (P < 0.05). Among SLE patients, the CHO-CD80/CHO ratio of patients with lupus nephritis was significantly higher than that of patients without lupus nephritis (P < 0.05). In conclusion, our data suggest that CTLA4 expression is not impaired in SLE patients, but there is a possibility of decreased inhibitory effect of CTLA4 involved in the pathogenesis of SLE.
Lupus 2004
PMID:Expression and activity analyses of CTLA4 in peripheral blood lymphocytes in systemic lupus erythematosus patients. 1487 Sep 14

The autoimmune response is executed via cognate interactions between effector immune cells and antigen presenting cells. Cognate interactions provide the immune effectors with specific signals generated through the antigen receptor as well as with second, non-specific signals, generated from the interaction of pairs of cell-surface molecules (costimulatory molecules) present on their plasma membrane. Disruption of this second, non-specific costimulatory signal results in the interruption of the productive (auto)immune response, leading to anergy, a state of immune unresponsiveness. The CD28:B7 families of molecules and the CD40:CD40L pair of molecules are considered as critical costimulatory elements. Disruption of the CD28:B7 interaction using a genetically engineered soluble form of the inhibitory molecule CTLA4 in vitro, as well as in experimental models of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), led to the inhibition of the autoimmune response. Similarly, promising data stem from the use of an anti-CD40L monoclonal antibody (mAb) in murine SLE. While such treatments prevent the development of autoimmunity in animal models, this preventive approach is inapplicable to human diseases. However, the rational bench-to-bedside approach led investigators to clinical trials of CTLA4-Ig and of two different humanized anti-human CD40L mAbs in patients with RA and SLE, respectively. Initial experience with the use of CTLA4-Ig in patients with RA is encouraging, since in one short-term trial the construct was well-tolerated and produced clinically meaningful improvement of the disease in a significant proportion of those treated. Surprisingly, the anti-CD40L mAb treatment approach in human lupus was not fruitful, since short-term administration of the anti-CD40L mAb ruplizumab in lupus nephritis was correlated with life-threatening prothrombotic activity despite initial encouraging data in the serology and renal function of the patients. Also, IDEC-131 anti-CD40L mAb treatment did not prove to be clinically effective in human SLE, despite being well tolerated. Precise tailoring of the administration schemes for these novel therapeutic modalities is awaited.Finally, conceptually different approaches to block costimulation by inhibiting the induced expression of costimulatory molecules or the transmission of their specific intracytoplasmic signal have already produced encouraging preliminary results.
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PMID:Costimulation blockade in the treatment of rheumatic diseases. 1504 25

B cell-activating factor belonging to the TNF family (BAFF) blockade prevents the onset of disease in systemic lupus erythematosus (SLE)-prone NZB/NZW F(1) mice. To determine the mechanism of this effect, we administered a short course of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F(1) mice and evaluated the effect on B and T cell subsets and on anti-dsDNA Ab-producing B cells. Even a brief exposure to TACI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect. The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG levels. However, after cessation of treatment, high titers of IgG anti-dsDNA Abs appeared in the serum and IgG Abs deposited in the kidneys. Despite the appearance of pathogenic autoantibodies, the onset of proteinuria was markedly delayed; this was associated with prolonged depletion of B cells past the T1 stage, a decrease in the size of the spleen and lymph nodes, and a decrease in the absolute number of activated and memory CD4(+) T cells. TACI-Ig treatment normalized serum levels of IgM that are markedly elevated in NZB/W F(1) mice; this appeared to be due to a prolonged effect on the ability of the splenic microenvironment to support short-lived IgM plasma cells. Finally, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in aged NZB/W F(1) mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.
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PMID:Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. 1532 17

Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation, and may help to limit T cell response under conditions of inflammation. Genetic variability in CTLA-4 has been implicated in the development of several autoimmune diseases. Some studies have described associations between CTLA-4 polymorphisms and systemic lupus erythematosus (SLE), but findings have been inconsistent. We examined polymorphisms in the CTLA-4 gene promoter region (-1722T/C, -1661 A/G, -318C/T) and exon I (+49G/A) with respect to SLE in a population-based case-control study in the southeastern US. Genotypes from 230 recently diagnosed cases and 276 controls were examined separately for African-Americans and whites. We observed no overall associations between SLE and the four CTLA-4 polymorphisms examined. Subgroup analyses revealed effect modification by age for the presence of the -1661G allele, yielding a significant positive association with SLE in younger (<35 years) African-Americans (OR = 3.3). CTLA-4 genotypes also interacted with HLA-DR2 and GM allotype to contribute to risk of SLE. These findings suggest allelic variation in this region of CTLA4 is not a major independent risk factor for SLE, but may contribute to risk of disease in younger African-Americans or in the presence of certain immunogenetic markers.
Lupus 2004
PMID:CTLA-4 gene polymorphisms and systemic lupus erythematosus in a population-based study of whites and African-Americans in the southeastern United States. 1554 May 11


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