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

We have recently reported that transforming growth factor-beta (TGF-beta) co-stimulates interleukin-2 (IL-2) activated CD8+ T cells to down-regulate antibody production. In SLE, lymphocyte production of both IL-2 and TGF-beta is decreased. Here we report that a brief treatment of PBMC from SLE patients with IL-2 and TGF-beta can result in marked inhibition of spontaneous polyclonal IgG and autoantibody production. Peripheral blood mononuclear cells (PBMC) from 12 patients with active SLE were exposed to IL-2 with or without TGF-beta for three days, washed and cultured for seven more days. The mean decrease in IgG secretion was 79%. The strongest inhibitory effect was observed in cases with the most marked B cell hyperactivity. Spontaneous production of anti-nucleoprotein (NP) antibodies was observed in four cases and cytokine treatment of PBMC decreased autoantibody production by 50-96%. IL-2 inhibited Ig production by either TGF-beta-dependent or independent mechanisms in individual patients. In a study of anti-CD2 stimulated IgG production in a patient with active SLE, we documented that IL-2 and TGF-beta reversed the enhancing effects of CD8+ T cells on IgG production and induced suppressive activity instead. These results raise the possibility that cytokine-mediated down-regulation of B cell hyperactivity in SLE may have therapeutic potential.
Lupus 1999
PMID:Cytokine-mediated down-regulation of B cell activity in SLE: effects of interleukin-2 and transforming growth factor-beta. 1019 2

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased production of antibodies reactive with a variety of self and non-self antigens. A number of immunomodulatory therapies have been investigated for the disease process. Intragastric administration of low dose kidney extract (KE) three times weekly for 5 weeks and then weekly until 6 months of age in SLE mice, showed decreased anti-dsDNA antibody levels, less kidney damage and significantly prolonged survival compared with control phosphate buffered saline (PBS)-fed mice. The KE-fed mice also exhibited reduced T cell proliferative response to KE in comparison with PBS-fed controls. Serum isotype distribution of the anti-dsDNA antibodies revealed a marked reduction of IgG1 and IgG3 responses in the KE-fed mice. While the renal inflammatory cell infiltration and expression of interleukin-4 (IL-4) and IL-10 were markedly suppressed, no local enhancement of transforming growth factor-beta (TGF-beta) was detected. Oral administration of low dose KE, however, upregulated expression of IL-2, IFN-gamma and TNF-alpha in the kidneys and suppressed glomerulonephritis. These findings suggest that oral KE affects the disease process in SLE and raise the possibility that oral administration of KE or other potential autoantigens may provide a new approach for the treatment of SLE.
 ...
PMID:Suppression of systemic lupus erythematosus disease in mice by oral administration of kidney extract. 1058 56

Natural killer (NK) cells are a third lymphocyte population especially important in innate immunity. NK cells may also have an important role in the regulation of acquired immunity. These lymphocytes spontaneously produce large amounts of both active and latent transforming growth factor-beta (TGF-beta). NK-cell-derived TGF-beta1 enabled activated CD8(+) T cells to inhibit antibody production by blocking the induction of this response. Production of lymphocyte-derived TGF-beta is decreased in systemic lupus erythematosus. Insufficient levels of this cytokine in SLE and other autoimmune diseases may contribute to defective T regulatory cell function characteristic of this and other autoimmune diseases. NK cells are found in mucosal tissues and the TGF-beta spontaneously released by these cells could contribute to the usual tolerogenic response of T cells to antigens presented at these sites. Thus, in addition to its well known immunosuppressive effects, TGF-beta could have an equally important role in the generation of regulatory T cells.
 ...
PMID:Role of NK cells and TGF-beta in the regulation of T-cell-dependent antibody production in health and autoimmune disease. 1061 59

We have previously observed that aged lupus-prone (NZB/NZW)Fl (BWF1) mice when infected with Plasmodium chabaudi show an improvement in their clinical lupus-like symptoms. In order to study the mechanisms involved in the long-lasting protective effect of the P. chabaudi infection in lupus-prone mice we analysed specific aspects of the cellular response, namely the profiles of cytokine mRNA expression and cytokine secretion levels in old BWF1 mice, in comparison with uninfected age-matched BWF1 mice and infected or uninfected BALB/c mice. Two months after infection, cells from BWF1 mice were stimulated with concanavalin A (Con A) and demonstrated a recovery of T cell responsiveness that reached the levels obtained with BALB/c cells. Old BWF1 mice showed high levels of interferon-gamma (IFN-gamma) and IL-5 production and correspondingly low levels of IL-2 and IL-4 secretion before infection with P. chabaudi. Infection did not modify the IFN-gamma levels of BWF1 T cells, whereas it considerably increased the secretion of the Th2-related cytokines IL-4, IL-5 and IL-10. In addition, only BWF1 T cells showed increased mRNA expression of tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta). This counter-regulatory cytokine network of infected BWF1 mice may be involved in the improvement of their lupus symptoms. The results of our investigations using the complex model of P. chabaudi infection can be extended and, by using more restricted approaches, it may be possible to explain the multiple regulatory defects of lupus-prone mice.
 ...
PMID:Changes in the cytokine profile of lupus-prone mice (NZB/NZW)F1 induced by Plasmodium chabaudi and their implications in the reversal of clinical symptoms. 1063 72

Although elevated levels of transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) have been implicated in renal disease, the tissue distribution and cellular localization of the induced cytokines is not well established. In this study, we investigated the expression of these cytokines during the progression of lupus nephritis in MRL lpr/lpr mice. The concentration of both cytokines increased in the plasma of these animals in an age-dependent manner, and there was an age-dependent induction of TGF-beta and TNF-alpha mRNAs in their kidneys. Although the increase in TGF-beta mRNA was specific for the kidney, the increase in TNF-alpha mRNA was widespread and also could be demonstrated in the liver, lung, and heart. In situ hybridization analysis of renal tissues from the lupus-prone mice localized TGF-beta mRNA to the glomerulus, and more specifically, to resident glomerular cells and inflammatory cells infiltrating periglomerular spaces in the nephritic lesions. The signals for TNF-alpha mRNA were detected only in inflammatory cells and were distributed throughout the nephritic kidney. Plasminogen activator inhibitor-1 (PAI-1) is known to be elevated in the glomeruli of MRL lpr/lpr mice, and intraperitoneal administration of either TGF-beta or TNF-alpha into normal mice markedly induced the expression of this potent inhibitor of fibrinolysis in renal glomerular or tubular cells in vivo. These results suggest that the increased renal expression of both cytokines may contribute to the development of lupus nephritis in this model and raise the possibility that PAI-1 may be involved. The fact that TGF-beta is specifically induced in the kidney whereas TNF-alpha increases in a variety of tissues, supports the hypothesis that the renal specificity of this disorder reflects the abnormal expression of TGF-beta.
 ...
PMID:Expression of transforming growth factor-beta and tumor necrosis factor-alpha in the plasma and tissues of mice with lupus nephritis. 1104 73

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.
 ...
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

Pulmonary fibrosis is characterized by the accumulation of excessive connective tissue in the lungs. Its causes include chronic administration of some drugs for example bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine, gold and nitrofurantoin; exposure to certain environmental factors such as gases, asbestos and silica and bacterial or fungal infections. Some systemic diseases also predispose to the disease for example rheumatoid arthritis and systemic lupus erythematosus. The disease is associated with release of oxygen radicals and some mediators such as tumor necrosis factor-alpha TNF-alpha, transforming growth factor-beta TGF-beta, PDGF, IGF-I, ET-I and interleukins 1, 4, 8 and 13. The symptoms of the disease include dyspnea, non-productive cough, fever and damage to the lung cells. It is diagnosed with the aid of chest radiography, high resolution computed tomographic scanning and the result of pulmonary function tests. Drug-induced pulmonary fibrosis may involve release of free oxygen radicals and various cytokines for example IL-Ibeta and TNF-alpha via activation of nuclear transcription factor NF-beta as in the case of bleomycin and mitomycin or via release of TGF-beta as in case of tamoxifen or via inhibition of macrophages' and lymphocytes' phospholipases as in the case of amiodarone with the resultant accumulation of phospholipids and reduction of the immune system.
 ...
PMID:Drug-induced pulmonary fibrosis. 1519 96

Immunization with portions of a murine antibody to DNA induced Ig peptide-reactive peripheral CD8+ inhibitory T (Ti) cells in non-autoimmune (BALB/c x NZW) F1 (CWF1) mice. Those Ti suppressed in vitro production of IgG anti-DNA by lymphocytes from MHC-matched, lupus-prone (NZB x NZW) F1 (BWF1) mice, primarily via secretion of transforming growth factor-beta (TGF-beta). However, splenic CD8+ cells from immunized BWF1 mice failed to suppress anti-DNA. Therefore, BWF1 mice were studied for defects in peripheral CD8+ T cells. The potential to suppress autoimmunity mediated by activated CD4+ helper T and B cells in BWF1 mice was assessed. As BWF1 mice aged, peripheral CD8+ T cells expanded little; fewer than 10% displayed surface markers of activation and memory. In contrast, quantities of splenic CD4+ T and B cells increased; high proportions displayed activation/memory markers. In old compared to young BWF1 mice, splenic cell secretion of two cytokines required for generation of CD8+ T effectors, IL-2 and TGF-beta, was decreased. Immunizing BWF1 mice activated peptide-reactive CD8+ T cells, but their number was decreased compared to young BWF1 or old normal mice. While peptide-reactive splenic CD8+ T cells from immunized BWF1 mice did not survive in short-term cultures, similar CD8+ T cell lines from immunized CWF1 mice expanded and on transfer into BWF1 mice delayed autoimmunity and prolonged survival. Therefore, CD8+ T cells in old BWF1 mice are impaired in expansion, acquisition of memory, secretion of cytokine, and suppression of autoimmunity. Understanding these defects might identify targets for therapy in systemic lupus erythematosus.
 ...
PMID:Differences between CD8+ T cells in lupus-prone (NZB x NZW) F1 mice and healthy (BALB/c x NZW) F1 mice may influence autoimmunity in the lupus model. 1530 81

To evaluate the T-cell large-scale differential gene expression in systemic lupus erythematosus (SLE) patients presenting with glomerulonephritis we studied SLE patients before and after immunosuppressive treatment. Large-scale gene expression of peripheral blood mononuclear T cells was evaluated using cDNA microarray nylon membranes containing 5184 cDNAs. Data were analysed using the SAM and Cluster and Treeview software. When untreated patients were compared to healthy individuals, 38 genes, most of them located on chromosomes 1, 3, 6, 17 and 19, were repressed, and when untreated patients were compared to treated ones, 154 genes, located on chromosomes 1, 6, 7, 12 and 17, were induced. In terms of biological function of coded proteins, the differentially expressed genes were associated with apoptosis, cell cycle, chromosomal scaffold, cytokine/chemokine, DNA repair/replication, Golgi/mitochondrial proteins, mRNA processing, signalling molecules and tumour suppressors. Two autoantigen genes related to RNA splicing (small nuclear riboprotein 70,000 MW-U1 SNR, and splicing factor 3a, 60,000 MW), and the tetranectin-plasminogen-binding protein were repressed. The Fc fragment of immunoglobulin G low affinity IIb, apoptotic protease activating factor-1, two subunits of cytochrome c, caspase 8, complement C5a, HLA-DRA, HLA-DQB1, transforming growth factor-beta receptor II, small nuclear ribonucleoprotein polypeptide N (Sm protein N) genes, heterogeneous nuclear riboprotein-C, and argininosuccinate lyase genes, among others, were induced. A total of 10 genes were repressed in untreated patients and induced in treated ones, among them tumour necrosis factor (ligand) superfamily member 9, tumour protein p53, mannosidase alpha class IA, and CD22. Although some of these differentially expressed genes are typically expressed in B cells, CD22 and CD32 have also been reported in T cells and may provide regulatory signals to B cells. Assessment of differential gene expression may provide hybridization signatures that may identify susceptibility, diagnostic and prognostic markers of SLE.
 ...
PMID:Immunosuppressive therapy modulates T lymphocyte gene expression in patients with systemic lupus erythematosus. 1531 40

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5'-monophosphate dehydrogenase, has several immunosuppressant actions. MPA depletes guanosine and deoxyguanosine nucleotides preferentially in T and B lymphocytes, inhibiting proliferation and suppressing cell-mediated immune responses and antibody formation, major factors in acute and chronic rejection. MPA also can induce T-lymphocyte apoptosis. MPA suppresses dendritic cell maturation and can induce human monocyte-macrophage cell line differentiation, decreasing the expression of interleukin (IL)-1 and enhancing expression of the IL-1 receptor antagonist. In addition, MPA inhibits adhesion molecule glycosylation and expression and lymphocyte and monocyte recruitment. Activated macrophages produce nitric oxide (NO) and superoxide, which combine to generate tissue-damaging peroxynitrite. MPA depletes tetrahydrobiopterin and decreases NO production by inducible NO synthase without affecting constitutive NO synthase activity. By these mechanisms, MMF exerts anti-inflammatory activity, which could attenuate both acute and chronic rejection. Unlike calcineurin inhibitors, MMF is nonnephrotoxic and does not induce transforming growth factor-beta production, which is fibrogenic. MMF inhibits arterial smooth muscle cell proliferation, a contributor to graft proliferative arteriopathy, and does not increase blood pressure, cholesterol, or triglyceride levels. By decreasing high-density lipoprotein oxidation and macrophage recruitment, MMF also may delay onset/progression of graft atherosclerosis. Thus, MMF may prevent chronic rejection by several mechanisms. MMF activity is synergistic with that of other agents such as valganciclovir for treating cytomegalovirus infection. MMF also has synergistic activity with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists in the treatment of some nephropathies in experimental animals. This combination may prevent progression toward end-stage renal disease in humans with chronic allograft, lupus, and diabetic nephropathies.
 ...
PMID:Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. 1625 60


<< Previous 1 2 3 4 Next >>