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)

To investigate the effects of overproduction of IL-12p40, a potent antagonist against IL-12, on lupus-like autoimmune disease in vivo, we generated p40 transgenic MRL-Fas(lprcg)/Fas(lprcg) mice. Serum p40 and IL-12 levels were 600- to 8000-fold and 3- to 20-fold higher in transgenic (p40-lpr(cg)) than nontransgenic (lpr(cg)) mice, respectively. Serum IFN-gamma levels increased after 3 months of age in lpr(cg) and this age-related increase was completely abrogated in p40-lpr(cg). Serum IL-4 levels were the same in both mice. Production of IgM and IgG anti-double-stranded DNA (dsDNA) antibodies was significantly lower in p40-lpr(cg). Anti-dsDNA antibodies decreased in Th1-dependent IgG2a but increased in the Th2-dependent IgG1 subclass significantly in p40-lpr(cg). Proteinuria, glomerulonephritis, and survival were only marginally ameliorated in p40-lpr(cg). The results suggest that excess p40 production in vivo may suppress Th1 responses in autoantibody and IFN-gamma production but lead to minimal improvement of clinical manifestations of autoimmune disease in this mouse model.
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PMID:Clear suppression of Th1 responses but marginal amelioration of autoimmune manifestations by IL-12p40 transgene in MRL-FAS(lprcg)/FAS(lprcg) mice. 1152 74

The production of type 1 (IFN-gamma, IL-2) and type 2 (IL-4, IL-5, IL-10, IL-13) cytokines by CD8(-) and CD8(+) T cells from systemic lupus erythematosus (SLE) patients and normal subjects was investigated using an intracellular cytokine-staining technique. This flow cytometric method facilitates analysis of both surface markers and cytoplasmic cytokines, after a short term (6 h) culture with or without phorbol myristate acetate and ionomycin (PMA/I) stimulation. In SLE patients, more unstimulated T cells produced IL-10 in comparison with controls; other cytokines were not detected in unstimulated cells. The percentage of IL-10-secreting T cells did not significantly increase after PMA/I stimulation of cells from SLE patients. The mean intensity of fluorescence (MIF) of intracellular IL-4 staining was significantly higher in CD8(-) T cells of SLE patients than controls. Significantly fewer CD8(-) and CD8(+) T cells from SLE patients secreted IFN-gamma after PMA/I stimulation compared with controls. The MIF and percentage of IL-2, IL-5, and IL-13-secreting cell subsets were not significantly different between SLE patients and controls. These findings indicate that T cells of SLE patients are already stimulated to produce IL-10 in vivo, which may result in downregulation of IFN-gamma secreting CD8(-) and CD8(+) T cells observed following PMA/I stimulation. Thus, the population size of Th1 and Tc1 cells are reduced in SLE patients whereas the effector function of Th2 cells, with respect to IL-4 production, is enhanced in SLE patients. Furthermore, although the balance between Th1/Th2 and between Tc1/Tc2 is disrupted in SLE patients, it is significantly biased in favour of the Th2 subset only.
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PMID:Quantitative and qualitative analysis of the balance between type 1 and type 2 cytokine-producing CD8(-) and CD8(+) T cells in systemic lupus erythematosus. 1159 Nov 24

The revival of thalidomide began shortly after the drug was withdrawn from the market because of its teratogenic properties. Therapeutic effects of thalidomide were found accidentally in leprosy patients with erythema nodosum leprosum (ENL). Subsequent research widened the understanding of the activity of thalidomide, and with improved methodology and the augmented background knowledge of immunology it was possible to interpret the properties of thalidomide more coherently. Effects on tumour necrosis factor-alpha (TNFalpha) release play an important role in the ability of thalidomide to affect the immune system. Alteration of synthesis and release of cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and interferon-gamma is involved in the complex mechanisms of thalidomide. Thalidomide targets leucocytes, endothelial cells and keratinocytes, affecting them in a different manner and at different cellular levels. Changes in the density of adhesion molecules alter leucocyte extravasation and the inflammatory response in the tissue involved. Several mechanisms for the teratogenic action of thalidomide are currently under review, but this mode of action of the drug still remains unclear and we review evidence-based hypotheses for the teratogenicity of thalidomide. Thalidomide shows significant clinical impact in several diseases such as ENL in lepromatous leprosy, chronic graft-versus-host disease, systemic lupus erythematosus, sarcoidosis, aphthous lesions in HIV infection, wasting syndrome in chronic illness, inflammatory bowel disease, multiple myeloma and some solid tumours. In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects. However, despite the promising findings of thalidomide at the molecular level, namely its anti-TNFalpha properties and its intercalation with DNA, and activity in clinical trials, there is still a great need for more intensive research.
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PMID:Theoretical basis for the activity of thalidomide. 1160 49

The potential of oral treatment with AVEMAR (AVEMAR), a new benzoquinone-containing fermentation product of wheat germ, on features of experimental systemic lupus erythematosus (SLE) in naive mice, induced by idiotypic manipulation, was studied. We assessed the effect of AVEMAR on the profile of autoantibody production and the response of Th1/Th2 related cytokines as well as the clinical picture of experimental SLE in the SLE-induced mice. When the product was given in the pre-immunization period, down-regulation of autoantibody production (anti-dsDNA, mouse 16/6 Id, and anti-histones) following treatment with AVEMAR was noted (eg anti-dsDNA decreased from 0.898+/-0.097 OD at 405 nm to 0.519+/-0.103 OD following treatment). This effect was sustained for at least 4 weeks after discontinuation of the therapy. Serological manifestations associated with a delay in Th2 response (IL-4 and IL-10) were recorded (eg IL-4 decreased from 91.7+/-8.11 to 59.55+/-7.78 ng/ml in splenocyte condition media). The mice showed normal ESR, WBC and less than 100 mg/dl of protein in the urine in comparison to > 300 mg/dl protein in the SLE non-treated mice. In conclusion, oral intake of AVEMAR can ameliorate the clinical manifestations of experimental SLE, via affecting the Th1/Th2 network inhibiting Th2 response.
Lupus 2001
PMID:AVEMAR (a new benzoquinone-containing natural product) administration interferes with the Th2 response in experimental SLE and promotes amelioration of the disease. 1167 50

In recent years there has been an effort to understand possible noncalcemic roles of vitamin D, including its role in the immune system and, in particular, on T cell-medicated immunity. Vitamin D receptor is found in significant concentrations in the T lymphocyte and macrophage populations. However, its highest concentration is in the immature immune cells of the thymus and the mature CD-8 T lymphocytes. The significant role of vitamin D compounds as selective immunosuppressants is illustrated by their ability to either prevent or markedly suppress animal models of autoimmune disease. Results show that 1,25-dihydroxyvitamin D3 can either prevent or markedly suppress experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. In almost every case, the action of the vitamin D hormone requires that the animals be maintained on a normal or high calcium diet. Possible mechanisms of suppression of these autoimmune disorders by the vitamin D hormone have been presented. The vitamin D hormone stimulates transforming growth factor TGFbeta-1 and interleukin 4 (IL-4) production, which in turn may suppress inflammatory T cell activity. In support of this, the vitamin D hormone is unable to suppress a murine model of the human disease multiple sclerosis in IL-4-deficient mice. The results suggest an important role for vitamin D in autoimmune disorders and provide a fertile and interesting area of research that may yield important new therapies.
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PMID:Vitamin D: its role and uses in immunology. 1172 33

Neutralization of TNF-alpha in humans with rheumatoid arthritis or Crohn's disease has been associated with the development of humoral autoimmunity. To determine the effect of TNF-alpha neutralization on cell-mediated and humoral-mediated responses, we administered anti-TNF-alpha mAb to mice undergoing acute graft-vs-host disease (GVHD) using the parent-into-F(1) model. In vivo neutralization of TNF-alpha blocked the lymphocytopenic features characteristic of acute GVHD and induced a lupus-like chronic GVHD phenotype (lymphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable antihost CTL activity and required the presence of anti-TNF-alpha mAb for the first 4 days after parental cell transfer, indicating that TNF-alpha plays a critical role in the induction of CTL. Moreover, an in vivo blockade of TNF-alpha preferentially inhibited the production of IFN-gamma and blocked IFN-gamma-dependent up-regulation of Fas; however, cytokines such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest that a therapeutic TNF-alpha blockade may promote humoral autoimmunity by selectively inhibiting the induction of a CTL response that would normally suppress autoreactive B cells.
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PMID:In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL. 1173 98

Idiopathic or immune thrombocytopenic purpura (ITP) is characterized by antibody-mediated destruction of platelets. The etiology is unknown. We postulated that increased autoantibody production in ITP might be attributable to either increased or prolonged expression of CD40 ligand (CD40L, CD154) in T or B lymphocytes, as has been previously observed in systemic lupus erythematosus (SLE). In addition, we hypothesized that ITP is characterized by increased levels of interleukin 4 (IL-4), a prototypic Th2 cytokine which, along with CD40 ligation, is required for B cell differentiation and production of several IgG subclasses. Cell surface CD154 expression was measured in freshly-isolated and in vitro-activated peripheral blood lymphocytes of sixteen ITP patients and eight healthy volunteers. Plasma levels of IL-4 and the prototypic Th1 cytokine interferon-gamma (IFNgamma) were determined. We observed that CD154 expression in unstimulated and in vitro-activated lymphocytes did not differ between ITP patients and healthy controls. Plasma levels of the Th2 cytokine IL-4 were significantly higher in the ITP patients. These studies indicate that overexpression of CD154 in lymphocytes is unlikely to be a primary pathophysiological defect in most patients with ITP. The data support that in addition to cell membrane antigens such as CD154, soluble cytokines such as IL-4 should be considered as potential targets for therapy in this disease.
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PMID:Functional properties of lymphocytes in idiopathic thrombocytopenic purpura. 1175 3

Prostaglandins of the E series are known to suppress in vitro production of Th-1 cytokines such as interleukin-2 (IL-2) and interferon-gamma but have not been shown to suppress production of Th-2 cytokines such as IL-4 or IL-10. The present study used two new synthetic prostaglandin E(1) (PGE(1)) analogs with oral bioavailability, misoprostol (MP), and enisoprost (EP), to determine if these agents (1) exert suppressive effects in vitro on cytokine production by fresh unseparated mouse splenocytes and (2) are beneficial in vivo when used in conditions mediated by excessive Th-1 or Th-2 cytokine production. Preliminary in vitro studies demonstrated that both MP and EP can inhibit mitogen-stimulated Th-1 and Th-2 cytokine production in a dose-dependent fashion. Interestingly, at low doses, a stimulatory effect on interferon-gamma production was seen for both agents. In vivo studies tested the ability of parenteral administration of MP to alter outcome in the parent-into-F1 model of acute or chronic graft-vs-host disease (GVHD), entities thought to be mediated by excessive Th-1 or Th-2 cytokine production, respectively. Administration of MP to mice undergoing acute GVHD resulted in little detectable effect. However, in three independent experiments, MP administration in chronic GVHD mice consistently blocked GVHD-associated lymphoproliferation. In two of three experiments, GVHD-associated autoantibody production was significantly reduced. Variability between individual mice and between experiments suggests that dosing regimens and MP preparation are of critical importance. Nevertheless, these findings raise the possibility that MP may be of benefit in the treatment of human diseases characterized by excessive Th-2 cytokine production and humoral autoimmunity, for example, human lupus.
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PMID:Preliminary Studies of in vitro and in vivo Effects of Misoprostol on Th-1 and Th-2 Cytokine Production. 1185 7

To examine the possible effect of plasmapheresis on the ratio of Th1/Th2 type cytokine-secreting cells we recruited eight patients with active systemic lupus erythematosus into the present study. They all failed to respond to conventional therapy. A sensitive multiparametric flow cytometric analysis was used for the detection of intracellular IL-4, IL-10 and IFNgamma. Stimulated peripheral blood cells were analysed by this procedure. Plasmapheresis was performed every second day for three occasions, using a continuous flow type blood cell separator, and a total of 100 ml/body weight kg plasma was removed. Patients received 1 mg/kg/day methylprednisolone during this period. As a result of the procedure, the rate of IFNgamma positive Th cells increased, while the rate of IL-4 and IL-10 expressing CD4 positive cells decreased. Together with these observations the concentration of anti-ds-DNA antibodies decreased after plasmapheresis. A decrease in disease activity index (SLE-DAI) indicated the clinical effectiveness of the therapy.
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PMID:Plasmapheresis modulates Th1/Th2 imbalance in patients with systemic lupus erythematosus according to measurement of intracytoplasmic cytokines. 1190 7

Sairei-to, one of the Japanese-Chinese herbal medicines has been used for the treatment of various diseases, especially collagen disease and edema in nephrotic syndrome. However, the mechanism of the therapeutic effects remains uncertain. Therefore, we investigated the immunological changes of skin, kidney, spleen cells and serum in autoimmune-prone MRL/lpr, MRL/n and C57BL/6J mice treated with Sairei-to. In MRL/lpr mice treated with Sairei-to, the improvement of proteinuria, reduction in the number of hematoxylin bodies in kidney, and reduced serum levels of blood urea nitrogen were observed. These results indicate that Sairei-to can improve or inhibit the progression of lupus nephritis. The proportion of CD19 and the serum levels of IgG1, which is one of the pathogenesis of lupus dermatoses and lupus nephritis, were significantly reduced in Sairei-to-treated MRL/lpr mice. Therefore, it is suspected that the B cell function was suppressed by Sairei-to. In addition, CD4/8 ratio in spleen cells and the degree of lymphoproliferation in MRL/lpr mice also decreased. Interestingly, IL-4 producing spleen cells were increased significantly by ELISPOT assay, and IFN-gamma mRNA expressions were reduced in Sairei-to-treated MRL/lpr mice. Regarding the Th balance, an imbalance towards Th1 predominance may play a significant role in MRL/lpr mice, and the Th1 axis was suppressed and the Th2 axis became predominant in Sairei-to-treated MRL/lpr mice. On the other hand, Th2 cell type immunoglobulins (IgG1) were suppressed. These results suggested that Sairei-to is potential for impairing shifted Th1/Th2 balance and hypergammaglobulinemia resulting in therapeutic effects.
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PMID:Unique therapeutic effects of the Japanese-Chinese herbal medicine, Sairei-to, on Th1/Th2 cytokines balance of the autoimmunity of MRL/lpr mice. 1191 7


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