Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lupus is an Ab-mediated autoimmune disease. One of the potential contributors to the development of systemic lupus erythematosus is a defect in naturally occurring CD4(+)CD25(+) regulatory T cells. Thus, the generation of inducible regulatory T cells that can control autoantibody responses is a potential avenue for the treatment of systemic lupus erythematosus. We have found that nasal administration of anti-CD3 mAb attenuated lupus development as well as arrested ongoing lupus in two strains of lupus-prone mice. Nasal anti-CD3 induced a CD4(+)CD25(-)latency-associated peptide (LAP)(+) regulatory T cell that secreted high levels of IL-10 and suppressed disease in vivo via IL-10- and TFG-beta-dependent mechanisms. Disease suppression also occurred following adoptive transfer of CD4(+)CD25(-)LAP(+) regulatory T cells from nasal anti-CD3-treated animals to lupus-prone mice. Animals treated with nasal anti-CD3 had less glomerulonephritis and diminished levels of autoantibodies as measured by both ELISA and autoantigen microarrays. Nasal anti-CD3 affected the function of CD4(+)ICOS(+)CXCR5(+) follicular helper T cells that are required for autoantibody production. CD4(+)ICOS(+)CXCR5(+) follicular helper T cells express high levels of IL-17 and IL-21 and these cytokines were down-regulated by nasal anti-CD3. Our results demonstrate that nasal anti-CD3 induces CD4(+)CD25(-)LAP(+) regulatory T cells that suppress lupus in mice and that it is associated with down-regulation of T cell help for autoantibody production.
 ...
PMID:Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+ CXCR5+ follicular helper T cells. 1894 Nov 93

Previous studies have shown that treatment of ovariectomized females with 17-beta estradiol (E2) accelerates the development of autoimmunity in the (NZBxNZW)F(1) murine lupus model. Treatment with estrogenic organochlorine pesticides (OCPs) such as chlordecone produces a similar effect. Although it is reasonable to postulate that the effects of chlordecone and related OCPs on autoimmunity are due to their estrogenic effects, this has not been clearly demonstrated. The objective of this study was to compare effects of chlordecone and E2 on splenic T lymphocyte parameters plausibly related to autoimmunity; specifically, on T-cell phenotype and functions. Ovariectomized (NZBxNZW)F(1) mice were treated for 6 weeks with implanted sustained-release pellets containing chlordecone or E2 at dosing rates shown previously to significantly shorten time to onset of disease. E2, but not chlordecone, increased the percentage of activated and memory CD4 T-cells, and reduced naive CD4 T-cells. E2 also elevated CD25 and glucocorticoid-induced TNF receptor (GITR) levels in CD4 T-cells, an effect not shared by chlordecone. On the other hand, both chlordecone and E2 increased Bcl-2 expression in CD4 T-cells and reduced CD4 T-cell apoptosis without affecting their proliferation. Although both treatments increased TNF-alpha and IL-2 secretion by CD4 T-cells, only chlordecone increased secretion of IFN-gamma and GM-CSF. E2, but not chlordecone, increased IL-10 secretion. These observations indicate that although it is considered an estrogenic OCP, chlordecone exerts effects on splenic T-cells that are different in a number of ways from E2.
 ...
PMID:Comparison of chlordecone and estradiol effects on splenic T-cells in (NZBxNZW)F(1) mice. 1895 62

Systemic lupus erythematosus (SLE) predominantly affects women, especially those in reproductive age. Genetic contributions to disease susceptibility as well as immune dysregulation, particularly persistent inflammatory responses, are considered essential features. Our aim was to determine whether human umbilical vein endothelial cells (HUVEC) isolated from healthy newborns to women with inactive SLE show inflammation-related abnormalities that might lead to an early development of SLE in the offsprings. HUVEC isolated from six women with inactive SLE were stimulated with 2.5 ng/mL of TNF-alpha and/or physiological and pharmacological doses of 17-I(2) estradiol (E2). Then the expression of VCAM-1, ICAM-1, E-selectin, toll-like receptor-9 (TLR-9), heat shock protein 70 (HSP70) and HSP90 were measured. The concentrations of IL-6, IL-8, and IL-10 were also determined in maternal serum and in TNF-alpha stimulated and non-stimulated HUVEC culture supernatant. HUVEC from children with no family history of autoimmune disease served as controls. Our results showed that in HUVEC from SLE+ mothers, a constitutively low expression of adhesion molecules was enhanced by TNF-alpha treatment. The E2 (1 ng/mL) increased the expression of adhesion molecules but had no effect upon TNF-alpha-treated cells. IL-6 was constitutively higher in SLE+ HUVEC, whereas IL-8 was lower; E2 treatment diminished the latter. The E2 had no effect upon IL-6 and IL-8 secretions in TNF-alpha-treated cells. SLE+ HUVEC showed a disordered cytoskeleton and overexpressed HSP70, HSP90, and TLR-9. Our results indicate that endothelial cells of newborns to SLE+ mothers are in a proinflammatory condition which can be upregulated by estrogens.
Lupus 2008 Dec
PMID:The altered expression of inflammation-related molecules and secretion of IL-6 and IL-8 by HUVEC from newborns with maternal inactive systemic lupus erythematosus is modified by estrogens. 1902 76

Since 1996, arsenic trioxide (As2O3) is used to treat patients with acute promyelocytic leukemia. We have recently shown that As2O3 is a novel promising therapeutic agent for the autoimmune diseases (human lupus-like syndrome) and the massive lymphoproliferation (human autoimmune lymphoproliferative-like syndrome) developed by MRL/lpr mice. As2O3 is able to achieve an almost complete regression of antibody- and cell-mediated manifestations in MRL/lpr mice. As2O3 eliminated the activated T lymphocytes responsible for lymphoproliferation and skin, lung, and kidney lesions. This treatment also markedly reduced anti-DNA autoantibodies, rheumatoid factor, IL-18, IFN-gamma, nitric oxide metabolites, TNF-alpha, Fas ligand and IL-10 levels, and immune-complex deposits in glomeruli, leading to significantly prolonged survival rates.
 ...
PMID:[New therapeutic perspectives for arsenic: from acute promyelocytic leukemia to autoimmune diseases]. 1903

Royal jelly (RJ) is a gelatinous secretion from young nurse worker bees (Apis mellifera), which serves as the sole food for the queen bee. Because of its pleiotropic functions for queen bees, RJ has also been used as a dietary supplement with various health benefits for humans. Because RJ is being indicated to have immunomodulatory potential for humans, we undertook the study to determine whether the oral administration of RJ could alter the development of systemic autoimmunity in New Zealand Black (NZB) x New Zealand White (NZW) F1 mice that genetically exhibit many manifestations similar to human systemic lupus erythematosus (SLE). We herein reported that mice administered with RJ showed a significant delay in the onset of the disease, as manifested by decreased proteinuria and a prolongation of lifespan. In addition, RJ administration after the onset of the disease significantly improved the renal symptoms, leading to an extended lifespan. RJ administration to mice caused a significant decrease in the serum level of IL-10, and in the autoantibodies against ssDNA, dsDNA and erythrocytes, as well as a reduction in the number of splenic autoreactive B cells. In conclusion, our data suggest that the use of RJ may be beneficial in the prevention of the early onset of SLE and in the control of the active progression of the manifestations of SLE.
Lupus 2009 Jan
PMID:Honeybee royal jelly inhibits autoimmunity in SLE-prone NZB x NZW F1 mice. 1907 68

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated immune responses mediated by T and B cells. A tolerogenic peptide, designated hCDR1, ameliorated the serological and clinical manifestations of SLE in mouse models of lupus. We investigated the role of B-cell activating factor (BAFF) in the beneficial effects of hCDR1. BAFF production was reduced in hCDR1-treated mice in association with diminished production of dsDNA-specific autoantibodies and proteinuria levels. In addition, IFN-gamma and IL-10, which induce BAFF secretion, were down-regulated in hCDR1-treated mice. The reduced levels of BAFF correlated with a lower rate of maturation and differentiation of B cells, and with a decrease in integrin expression and anti-apoptotic gene expression by B cells. Moreover, BAFF signaling through the NF-kB pathways was inhibited in hCDR1-treated mice. Thus, down-regulation of BAFF plays a role in the mechanism of action by which hCDR1 ameliorates lupus manifestations.
 ...
PMID:B-cell activating factor (BAFF) plays a role in the mechanism of action of a tolerogenic peptide that ameliorates lupus. 1918 92

We have previously reported that IL-10(+) regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the transitional 2 immature (T2) B cell pool (T2 Bregs). Therapeutic strategies facilitating their enrichment or enhancing their suppressive activity are highly attractive. In this study, we report that agonistic anti-CD40 specifically targets T2 B cells and enriches Bregs upon short-term in vitro culture. Although transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40-generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, induced the differentiation of IL-10(+)CD4(+)T cells, and conveyed a regulatory effect to CD4(+)T cells. In addition, in vivo administration of agonistic anti-CD40, currently on trial for the treatment of cancer, halted and reversed established lupus. Taken together, our results suggest a novel cellular approach for the amelioration of experimental lupus.
 ...
PMID:Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice. 1926 27

A tolerogenic peptide, hCDR1, ameliorated murine lupus via the upregulation of functional regulatory cells and by immunomodulating cytokine production. In the present study we analyzed the ability of hCDR1 to similarly affect gene expression and regulatory T cells when incubated with peripheral blood mononuclear cells (PBMC) of lupus patients. To this end, peripheral blood mononuclear cells (PBMC) of 11 lupus patients and five gender- and age-matched healthy controls were cultured with hCDR1 or a control peptide. Gene expression and regulatory T-cells were assessed. hCDR1 significantly downregulated interleukin (IL)-1beta, interferon (IFN)-gamma, and IL-10 gene expression. Furthermore, hCDR1 upregulated the expression of the anti-apoptotic Bcl-xL molecule and downregulated the pro-apoptotic caspase-3, resulting in reduced rates of apoptosis. hCDR1 increased the expression of transforming growth factor (TGF)-beta, FoxP3 and the negative regulators Foxj1 and Foxo3a. No significant effects were observed using a control peptide or when PBMC of healthy donors were incubated with hCDR1. The elevated gene expression of FoxP3 was due to hCDR1-induced upregulation of TGF-beta, resulting in an increase of CD4+CD25+FoxP3+ functional, regulatory cells. The ability of the regulatory cells to diminish IFN-gamma expression and to upregulate TGF-beta was abrogated after the addition of a neutralizing anti-CD25 antibody, confirming their role in the beneficial effects of hCDR1.
 ...
PMID:The tolerogenic peptide hCDR1 downregulates pathogenic cytokines and apoptosis and upregulates immunosuppressive molecules and regulatory T cells in peripheral blood mononuclear cells of lupus patients. 1928 Jul 12

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulation of cytokines, apoptosis, and B- and T-cell functions. The tolerogenic peptide, hCDR1 (Edratide), ameliorated the clinical manifestations of murine lupus via down-regulation of pro-inflammatory cytokines and apoptosis, up-regulation of the immunosuppressive cytokine TGF-beta, and the induction of regulatory T-cells. In the present study, gene expression was determined in peripheral blood mononuclear cells of 9 lupus patients that were treated for 26 weeks with either hCDR1 (five patients), or placebo (four patients). Disease activity was assessed by SLEDAI-2K and the BILAG scores. Treatment with hCDR1 significantly down-regulated the mRNA expression of the pathogenic cytokines IL-1beta, TNF-alpha, IFN-gamma, and IL-10, of BLyS (B-lymphocyte stimulator) and of the pro-apoptotic molecules caspase-3 and caspase-8. In contrast, the treatment up-regulated in vivo gene expression of both TGF-beta and FoxP3. Furthermore, hCDR1 treatment resulted in a significant decrease in SLEDAI-2K (from 8.0+/-2.45 to 4.4+/-1.67; P=0.02) and BILAG (from 8.2+/-2.7 to 3.6+/-2.9; P=0.03) scores. Thus, the tolerogenic peptide hCDR1, immunomodulates, in vivo, the expression of genes that play a role in SLE, consequently restoring the global immune dysregulation of lupus patients. Hence, hCDR1 has a potential role as a novel disease-specific treatment for lupus patients.
 ...
PMID:Treatment of lupus patients with a tolerogenic peptide, hCDR1 (Edratide): immunomodulation of gene expression. 1934 2

In animal models of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), the proportion of CD45RC T cell subsets is important for disease susceptibility. Their human counterparts are, however, functionally ill defined. In this report, we studied their distribution in healthy controls (HC), AAV patients and in Systemic lupus erythematous (SLE) patients as disease controls. We showed that CD45RC expression level on human CD4 and CD8 T cells identifies subsets that are highly variable among individuals. Interestingly, AAV patients exhibit an increased proportion of CD45RC(low) CD4 T cells as compared to HC and SLE patients. This increase is stable over time and independent of AAV subtype, ANCA specificity, disease duration, or number of relapses. We also analyzed the cytokine profile of purified CD4 and CD8 CD45RC T cell subsets from HC, after stimulation with anti-CD3 and anti-CD28 mAbs. The CD45RC subsets exhibit different cytokine profiles. Type-1 cytokines (IL-2, IFN-gamma and TNF-alpha) were produced by all CD45RC T cell subsets, while the production of IL-17, type-2 (IL-4, IL-5) and regulatory (IL-10) cytokines was restricted to the CD45RC(low) subset. In conclusion, we have shown that CD45RC expression divides human T cells in functionally distinct subsets that are imbalanced in AAV. Since this imbalance is stable over time and independent of several disease parameters, we hypothesize that this is a pre-existing immune abnormality involved in the etiology of AAV.
 ...
PMID:CD45RC isoform expression identifies functionally distinct T cell subsets differentially distributed between healthy individuals and AAV patients. 1938 Dec 93


<< Previous 1 2 3 4 5 6 7 8 9 10