Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the role of V beta 8+ T cells in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice, we treated them with the F23.1 anti-V beta 8 monoclonal antibody (mAb) from birth to 4 months of age. Here we report that almost complete depletion of V beta 8+ T cells by the F23.1 mAb treatment neither inhibited nor delayed the development of hypergammaglobulinemia, autoantibody production and autoimmune glomerulonephritis in MRL-lpr/lpr mice. In addition, the F23.1 mAb treatment did not prevent the development of lymphadenopathy and the generation of a CD4-CD8- double-negative T cell subset, characteristically accumulating in lpr lymph nodes. Our results strongly argue against the idea that the V beta 8+ T cells play a critical role in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice.
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PMID:Lack of association of V beta 8+ T cells with lupus-like syndrome in MRL-lpr/lpr mice. 802 33

Although precise diagnosis of the systemic vasculitides can provide general prognostic information and help to guide initial therapy, recent studies on the long-term clinical course have revealed considerable variation in clinical severity. Therefore, anatomic distribution of involvement and speed of progression should be the principle determinants of the intensity of immunosuppressive therapy. In progressive pulmonary or renal disease, eg, Wegener's granulomatosis, aggressive "standard" therapy is obligatory, eg, daily cyclophosphamide and glucocorticoids. Such regimens, however, should be applied with caution in chronic or indolent and abortive forms of systemic vasculitis, because follow-up studies (eg, in Wegener's granulomatosis) have revealed treatment-associated morbidity rates of up to 42%, disease-related morbidity, and a high incidence of relapse under treatment. Moreover, less toxic therapeutic strategies are being pursued with remarkable success: low-dose weekly methotrexate, monthly intravenous or oral pulses of cyclophosphamide plus glucocorticoids, and high-dose intravenous immunoglobulin. Long-term remission of intractable (non-antineutrophil cytoplasmic antibody-associated) systemic vasculitis has been achieved using humanized monoclonal antibodies (ie, anti-CD4/anti-CDw52); and amelioration of glomerulonephritis in immune complex diseases (eg, systemic lupus erythematosus) has been achieved with nafamostat mesilate, an inhibitor of complement serine proteases. In addition, leukocytoclastic vasculitis has been effectively controlled with pentoxifylline, presumably by neutralizing proinflammatory cytokines, and hepatitis C virus-associated mixed cryoglobulinemia has been successfully treated with interferon alfa.
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PMID:New developments in the treatment of systemic vasculitis. 803 74

To investigate the role of IL-6 in systemic lupus erythematosus (SLE), we selectively inhibited IL-6 in lupus-prone NZB/NZW F1(B/W) mice by chronic administration of a rat mAb to mouse IL-6. Anti-IL-6 alone elicited an anti-rat response that blocked its biologic effects. To circumvent this problem, we rendered B/W mice tolerant to the rat mAb by administration of anti-CD4 concurrent with the first dose of anti-IL-6. Thereafter, the mice received weekly injections of anti-IL-6 alone. There were two control groups: one group received the tolerizing regimen of anti-CD4 along with a control rat IgG1 mAb (GL113) instead of anti-IL-6; the other control group received PBS. Mice that received anti-CD4 were tolerant to the rat mAb for 6 mo. Throughout this period, treatment with anti-IL-6 prevented production of anti-dsDNA, significantly reduced proteinuria, and prolonged life. Mice that received anti-IL-6 without anti-CD4 developed an immune response to the rat mAb and then developed anti-dsDNA antibodies, proteinuria, and mortality comparable with control mice. These findings establish that IL-6 promotes autoimmunity in B/W mice. They further indicate that, although mAb to IL-6 can suppress murine lupus, the development of host immunity to the mAb abrogates its beneficial effects. Finally, this is the first study to demonstrate that a brief course of anti-CD4 can induce tolerance to another therapeutic mAb, in this case an anti-cytokine mAb.
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PMID:Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. 804 Mar 14

The clinical presentation, risk factors, laboratory data, and neuroimaging and neuropathological findings in 26 patients with autopsy proved central nervous system (CNS) aspergillosis are reviewed. Eleven patients had hematological malignancies (8 underwent bone marrow transplantation), 8 patients underwent liver transplantation, and 3 patients had acquired immunodeficiency syndrome. Four had illnesses resulting in immunosuppression (systemic lupus erythematosus, infected aortic graft, neuroblastoma, and fulminant hepatic failure). The most common presenting clinical symptoms of CNS aspergillosis were fever and a strokelike syndrome. Risk factors for developing CNS aspergillosis included neutropenia, immunosuppressive therapy, low CD4 counts, and retransplantation. Spinal fluid findings were nondiagnostic. Computed tomograms and magnetic resonance scans of the head showed low-density lesions or hemorrhagic infarctions. Most aspergillosis cases occurred in the setting of widely disseminated disease commonly arising from the lung. Pathologically, multiple areas of necrosis throughout the brain were seen. Aspergillus invasion of blood vessel walls was seen microscopically. Amphotericin B with or without flucytosine was not effective treatment.
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PMID:Central nervous system aspergillosis. Analysis of 26 patients. 806 80

An open clinical trial was designed to examine the efficacy and safety of lobenzarit (CCA), a newly developed disease modifying anti-rheumatic drug, in combination with conventional treatment with prednisolone for patients with systemic lupus erythematosus (SLE). Fifteen patients with SLE were given CCA 40 mg b.i.d. for the first 2 weeks, 80 mg b.i.d. for the next 4 weeks, and 80 mg t.i.d. or b.i.d. until the end of the 12-month trial, in addition to prednisolone, whose doses were kept unchanged throughout the trial. The patients' clinical responses to CCA, including alterations in various laboratory parameters and the development of complications, were evaluated at the end of 12 months. Fourteen of the 15 patients completed the 12-month trial. Significant increases in the white blood cell count and CD4/CD8 ratio, as well as decreases in serum anti-DNA antibody, were noted after the trial. Five patients presented with adverse effects, including mild liver dysfunction, gastrointestinal symptoms and dizziness. Only one patient who developed dizziness withdrew at 9 months. Eleven patients could be reevaluated after discontinuation of CCA, and only 2 of them have experienced recurrence of active disease 6 months after discontinuation. In one additional patient who had not responded to prednisolone 35 mg daily, administration of CCA resulted in improvement of the disease activity. These results indicate that CCA in combination with corticosteroids is a useful adjunct in the treatment of SLE. A placebo-controlled study will be necessary to confirm these results.
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PMID:Treatment of systemic lupus erythematosus with lobenzarit: an open clinical trial. 807 Jan 58

Extensive studies in lupus-prone mice strongly suggest that mAbs to CD4 may be effective in SLE. By virtue of their selectivity for distinct cells within the immune system, anti-CD4 mAbs may be both more potent and less toxic than current therapies for SLE. In addition, their potential to block the host immune response to therapy may provide a critical advantage for anti-CD4 compared to other forms of mAb therapy. The problem of generalized immune suppression remains a significant obstacle to the use of anti-CD4 in humans, but it may be minimized by the use of mAb fragments or mAb isotypes that can reversibly inhibit immune function without depleting CD4+ T cells.
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PMID:Treatment of murine lupus with anti-CD4 monoclonal antibodies. 809

Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) alpha, beta, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of alpha-Ii and beta-Ii chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, alpha-Ii and beta-Ii; (e) the displacement of Ii chains by peptides to form alpha-beta-peptide complexes in the endosome; and (f) the migration of alpha-beta-peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the alpha-beta-peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Lupus 1993 Feb
PMID:Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation. 809 45

MRL/Mp-lpr/lpr (MRL-lpr) mice have been used for a model of human systemic lupus erythematosus. This strain of mice homozygous for an autosomal recessive mutation, lpr (lymphoproliferation), develops massive lymphadenopathy with the expansion of CD4-CD8- (double negative; DN) T cells. Recently it was demonstrated that lpr mice have defects in the gene of Fas antigen which mediates apoptosis, indicating a possibility of defect in negative selection of autoreactive T cells in the thymus of lpr mice. However, the mechanisms that control the accumulation of DN T cells in lymph nodes, and the involvement of DN T cells in the clinical manifestation of disease, have not been well understood. In this study, the expression of various cell adhesion molecules on lymphocytes from MRL-lpr mice was examined. The strong expression of CD44 antigen as well as heat stable antigen (HSA) on abnormal DN T cells of lymph nodes was characteristic in MRL-lpr mice. Furthermore, the accumulation of DN T cells in lymph nodes might result from augmented binding of lymphocytes to endothelial cell surface of lymph nodes, possibly due to the failure of Mel-14 antigen shedding from DN T cell surface. In addition, it was found that monoclonal antibodies reactive with cell adhesion molecules such as CD44, Mel-14, CD45R and HSA expressed on DN T cells, could trigger the lytic activity of DN T cells and redirected DN T cell-mediated lysis of Fc-receptor-positive target cells (EL-4). In contrast to T cell receptor (TCR)-mediated cytotoxicity, this redirected cytotoxicity was not inhibited by anti-lymphocyte function associated antigen-1 (LFA-1) antibody. Thus, cell adhesion molecules may play a major role in delivering the transmembrane signal to DN T cells of MRL-lpr mice that trigger the lytic activity. It is likely that DN T cells of MRL-lpr mice induce tissue damages by the interaction with ligand on vascular endothelium or extracellular matrix in vivo.
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PMID:[Functional studies of adhesion molecules on CD4-CD8- double negative T cells of autoimmune MRL/Mp-lpr/mice]. 822 81

Different glucocorticoid preparations modify the immune reaction in different ways. In this paper, the therapeutic efficacy of two glucocorticoids, deflazacort (DFZ) and prednisone (PDN), are discussed in relation to a group of 30 patients with systemic lupus erythematosus (n = 12) or rheumatoid arthritis (n = 18). The disease sub-groups were divided into two arms, one of which was treated with DFZ and one with PDN in a double-blind protocol. The results of this study indicate that DFZ and PDN induced a clinical remission within 1 month which was maintained until the 6th month. Nevertheless, certain immunological modifications, including a significant reduction of the circulating T lymphocyte level and of the CD4/CD8 ratio, which was between 1 and 1,5 during the DFC treatment and between 1 and 2 during the PDN treatment, are more pronounced and more stable with DFZ than with PDN. Moreover, DFZ has a smaller effect on calcium and glucose metabolism than PDN since the serum glucose and calcium level of patients treated with PDN increased respectively from 90 up to 130 mg/dl and from 9,5 to 11,5 mg/dl whereas those of patients treated with DFC remained within the normal range. These findings indicate that DFZ may have advantages over PDN in the treatment of immune-mediated diseases.
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PMID:Comparison of two glucocorticoid preparations (deflazacort and prednisone) in the treatment of immune-mediated diseases. 831 31

The autosomal recessive mutant gene, lpr, has been shown to accelerate the progression of lupus-like autoimmune disease, which is associated with a massive expansion of a unique CD4-CD8- double-negative T cell subset, in MRL/MpJ mice. Here we report a substrain of MRL/MpJ-lpr/lpr (MRL-lpr) mice which live almost twice as long with delayed development of glomerulonephritis, compared with conventional MRL-lpr mice. This substrain, termed MRL-lpr.II (II for long-lived), develops generalized lymphadenopathy characteristically seen in MRL-lpr mice. However, the expansion of a double negative lpr T cell subset is markedly limited with a mean value of 15% in their lymph nodes compared to about 70% in conventional MRL-lpr mice. Overall production of autoantibodies, such as anti-DNA and rheumatoid factors, does not significantly differ between the two MRL-lpr mice. However, serum levels of cryoglobulins, whose major component is IgG3, are markedly diminished in MRL-lpr.II mice with a parallel decrease in IgG3. Since MRL-lpr.II mice still carry the lpr mutation, as documented by the presence of defects in the Fas antigen, a possible new mutation in this substrain may play a significant role in the pathogenesis of lupus-like autoimmune syndrome.
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PMID:An MRL/MpJ-lpr/lpr substrain with a limited expansion of lpr double-negative T cells and a reduced autoimmune syndrome. 831 55


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