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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although systemic lupus erythematosus (SLE) is indeed a complex autoimmune disease, recent advances in our understanding of lupus pathogenesis have suggested new, targeted approaches to therapy. The purpose of this review is to discuss the underlying scientific rationale and results of first clinical studies of new treatment approaches to SLE, with a focus on cell-depleting therapies and cytokine blockade. It has become clear that the B lymphocyte plays a key role in disease pathogenesis by both autoantibody-dependent and autoantibody-independent mechanisms. Additionally, aberrant interactions between B and T cells are critical to disease emergence and progression. New agents that directly target immune cells abnormal in SLE include the B-cell depleting or modulating antibodies, rituximab (anti-CD20) and epratuzumab (anti-CD22) and the anti-dsDNA tolerogen LJP394. Another promising approach has been to block co-stimulatory interactions between T and B cells, for example by inhibiting the CD40-CD40 ligand pathway with anti-CD40 ligand monoclonal antibody or the B7 pathway with CTLA-4Ig. Immune cells can also be manipulated indirectly through cytokine effects. For B cells, anti-BAFF (B-cell activation factor of the tumor necrosis family) provides an example of this approach. Other, more pleiotropic cytokines can likewise be blocked in SLE. In addition to the blockade of interleukin-10 (IL-10), the first anti-cytokine approach examined, it is mainly anti-tumor necrosis factor therapy that has come into focus, holding promise for some patients with lupus nephritis. The majority of the available data on these new treatment approaches stems from open-label trials, but controlled trials are under way. Moreover, many additional cytokines, such as interleukin (IL)-6, IL-18, and the type I interferons, represent interesting future targets.
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PMID:New treatments for SLE: cell-depleting and anti-cytokine therapies. 1615 Apr 7

We analyzed the activation and function of dendritic cells (DCs) in the spleens of diseased, lupus-prone NZM2410 and NZB-W/F1 mice and age-matched BALB/c and C57BL/6 control mice. Lupus DCs showed an altered ex vivo costimulatory profile, with a significant increase in the expression of CD40, decreased expression of CD80 and CD54, and normal expression of CD86. DCs from young lupus-prone NZM2410 mice, before the development of the disease, expressed normal levels of CD80 and CD86 but already overexpressed CD40. The increase in CD40-positive cells was specific for DCs and involved the subset of myeloid and CD8alpha+ DCs before disease onset, with a small involvement of plasmacytoid DCs in diseased mice. In vitro data from bone marrow-derived DCs and splenic myeloid DCs suggest that the overexpression of CD40 is not due to a primary alteration of CD40 regulation in DCs but rather to an extrinsic stimulus. Our analyses suggest that the defect of CD80 in NZM2410 and NZB-W/F1 mice, which closely resembles the costimulatory defect found in DCs from humans with systemic lupus erythematosus, is linked to the autoimmune disease. The increase in CD40 may instead participate in disease pathogenesis, being present months before any sign of autoimmunity, and its downregulation should be explored as an alternative to treatment with anti-CD40 ligand in lupus.
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PMID:Abnormal costimulatory phenotype and function of dendritic cells before and after the onset of severe murine lupus. 1650 74

Prolactin is of interest in the pathogenesis of systemic lupus erythematosus (SLE) because almost 25% of SLE patients display hyperprolactinemia, and serum prolactin correlates with disease activity in some patients. Furthermore, hyperprolactinemia causes early mortality in lupus-prone mice and induces a lupus-like phenotype in nonspontaneously autoimmune mice. We show here that the immunomodulatory effects of prolactin are genetically determined; hyperprolactinemia breaks B cell tolerance and causes a lupus-like serology in BALB/c mice expressing a transgene encoding the H chain of an anti-DNA Ab but not in C57BL/6 transgenic mice. In C57BL/6 mice that express both the H chain transgene and the lupus susceptibility interval Sle3/5, prolactin induces increased serum titers of anti-DNA Ab and glomerular Ig depositions. The increase in costimulation due to prolactin-mediated up-regulation of both CD40 on B cells and CD40L on T cells would appear to play a central role in lupus induction in this model.
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PMID:Cutting edge: lupus susceptibility interval Sle3/5 confers responsiveness to prolactin in C57BL/6 mice. 1684 43

CD30/CD30L and CD40/CD40L are molecules from the tumor necrosis factor (TNF) superfamily. They have a major effect on communications between the B and T cells, which leads to control of maturation, proliferation, and apoptosis of those cells. The aim of this study was to compare the levels of a soluble form of CD30 (sCD30) and a soluble ligand CD40 (sCD40L) in patients with systemic lupus erythematosus (SLE) (n=65) and healthy controls (sCD30 n=20, sCD40L n=10) with other parameters of SLE activity. Patients were divided into subgroups according to presence or absence of lupus nephritis (LN; 33 with LN, 32 without LN). The serum levels of selected parameters were assessed also in the subgroups with low active disease characterized by European Lupus Activity Measure (ECLAM) at most 3(n=29) and active disease with ECLAM more than 3 (n=36). The serum levels of sCD30 were 66.0+/-40.2 UI/ml in the whole group. The mean serum levels were 60.0+/-45.2 UI/ml in the subgroups with LN, 67.1+/-38.9 UI/ml in the subgroup without LN, 80.2+/-51.9 UI/ml in the subgroup with active disease, 55.4+/-24.1 UI/ml in the subgroup with low active disease, and finally, 40.1+/-19.2 U/ml in the controls. Significant differences were found between the SLE patients and controls (p=0.0001) and between the active and nonactive groups (p=0.002). A correlation was found between levels of CD30 and ECLAM (r=0.25, p<or=0.05), SLEDAI (SLE Disease Activity Index) (r=0.25, p<or=0.05), C4 component of the complement system (r=0.24, p=0.02), and anti-C1q antibodies (r=0.42, p=0.0001). The levels of sCD40L were 7.4+/-6.7 ng/ml in whole SLE group, 7.0+/-8.1 ng/ml in the subgroup with LN, 8.0+/-4.9 ng/ml in the subgroup without LN, 7.1+/-5.0 ng/ml in the group of patients with active disease, 7.73+/-7.8 ng/ml in the subgroup with low activity, and 2.96+/-1.39.0 ng/ml in the controls. The difference in sCD40L serum levels between patients with SLE and controls was statistically significant (p=0.02). A correlation was found with the anti-C1q antibodies (r=0.21, p=0.05); no other correlations were found. These findings indicate some potential role of both serum parameters in measurement or SLE disease activity, although their usage in the diagnostic of disease requires further investigation.
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PMID:The levels of sCD30 and of sCD40L in a group of patients with systemic lupus erythematodes and their diagnostic value. 2752 Jul 3

The main goal of therapy for lupus nephritis is to achieve remission, as this has a major impact on patient and renal survival. Furthermore, early treatment success has been shown to improve long-term prognosis. This has traditionally been achieved with intravenous cyclophosphamide, but recent data show that mycophenolate mofetil is equally effective and causes fewer adverse effects. Research is ongoing to find new treatment targets. Possible future therapies include monoclonal antibodies against CD20 (rituximab), CD22 (epratuzumab) and CD40, and therapies targeted at cytokine secretion, immunoglobulin secretion, B-cell maturation and T-cell proliferation and differentiation. Rituximab has shown promise in patients with active proliferative lupus nephritis, which suggests that B-cell depletion may be successful. Anti-double-stranded DNA antibodies correlate with flares of lupus nephritis and may represent another therapeutic target. Therapy with LIP 394, which crosslinks anti-double-stranded DNA antibodies in solution or on the B-cell surface, has been shown to reduce flares. Cardiovascular disease is a major cause of mortality in systemic lupus erythematosus, and this must also be addressed if long-term outcomes are to be improved. Many patients with systemic lupus erythematosus have subclinical atherosclerosis quite early in the disease course, and the risk of coronary artery disease at any level of traditional cardiovascular risk factors is higher than in the general population. Specific lupus-associated risk factors include the inflammatory process itself and anticardiolipin antibodies. Possible strategies to reduce the risk include reduction of disease activity to improve endothelial function and reduction of steroid dose whenever possible. Therapy with aspirin or statins may be another possibility. Thus treatment of lupus nephritis is evolving from standardised therapy to individualised therapy based on analysis of organ involvement, risk factors and cytokine, antibody or cell profiles.
Lupus 2007
PMID:Exploring new territory: the move towards individualised treatment. 1743 12

CD40/CD40L signaling promotes both B cell and CTL responses in vivo, the latter being beneficial in tumor models. Because CTL may also limit autoreactive B cell expansion in lupus, we asked whether an agonist CD40 mAb would exacerbate lupus due to B cell stimulation or would improve lupus due to CTL promotion. These studies used an induced model of lupus, the parent-into-F1 model in which transfer of DBA/2 splenocytes into B6D2F1 mice induces chronic lupus-like graft-vs-host disease (GVHD). Although agonist CD40 mAb treatment of DBA-->F1 mice initially exacerbated B cell expansion, it also strongly promoted donor CD8 T cell engraftment and cytolytic activity such that by 10 days host B cells were eliminated consistent with an accelerated acute GVHD. CD40 stimulation bypassed the requirement for CD4 T cell help for CD8 CTL possibly by licensing dendritic cells (DC) as shown by the following: 1) greater initial activation of donor CD8 T cells, but not CD4 T cells; 2) earlier activation of host DC; 3) host DC expansion that was CD8 dependent and CD4 independent; and 4) induction of acute GVHD using CD4-depleted purified DBA CD8+ T cells. A single dose of CD40 mAb improved lupus-like renal disease at 12 wk, but may not suffice for longer periods consistent with a need for continuing CD8 CTL surveillance. These results demonstrate that in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, CTL promotion is both feasible and beneficial and the CTL-promoting properties of CD40 stimulation outweigh the B cell-stimulatory properties.
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PMID:CTL-promoting effects of CD40 stimulation outweigh B cell-stimulatory effects resulting in B cell elimination and disease improvement in a murine model of lupus. 1856 69

Recent studies show that a CD8+CD28- phenotype of T-cell population inhibits the reactivity of T-helper cells either by a contact-dependent mechanism or with secreting suppressive cytokines. In this study, we have explored the peripheral blood CD8+CD28- T-cell population in 53 patients with systemic lupus erythematosus (SLE) in comparison to healthy and diseased control groups. The distribution of CD28- cells within CD8+ population has been found significantly lower in patients with SLE than in healthy individuals. While there were no significant differences in the expression of costimulatory molecules CD80 and CD86, the CD40 expression on monocytes was found significantly lower and there was a slight decrease of expression of Interleukin-10 (IL-10) in CD8+CD28- population in patients with SLE. The Transforming growth factor-beta (TGF-beta) mRNA expression was found higher in CD8+CD28- T cells. Neither activation induced nor time-dependent change in the frequency of CD8+CD28- cells has been observed following stimulation at various time-points indicating that the control of CD28 expression was not dependent on the presence of sustained stimulations. Decrease in CD8+CD28- T cells which normally produce TGF-beta and their low-level IL-10 content may reflect impaired T-cell suppression and accordingly, increased T cell help to autoreactive B cells in patients with SLE.
Lupus 2008 Jul
PMID:CD8+CD28-, suppressive T cells in systemic lupus erythematosus. 1862 35

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.
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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

Different immunological alterations may condition systemic lupus erythematosus (SLE) activity. However, it is not known whether alterations in the phenotype of circulating antigen-presenting cells (APCs) and in the response to CpG oligodeoxynucleotides (ODN-CpG) correlate with disease activity. APC expression of HLA-DR, costimulatory molecules, and TLR9 expression was determined in patients with SLE, other autoimmune diseases, and healthy controls. Monocyte and B cell response to synthetic ODN-CpG sequences was also evaluated. Monocytes from patients with moderate SLE activity had higher expression of CD40 and CD86. Decreased numbers of CD19+CD80+ and BDCA-3+CD40+ cells were found in patients with severe SLE activity. In patients with moderate SLE activity, non-adherent and enriched B cell response to ODN-CpG was similar to healthy controls. Adherent and enriched B cells from patients with severe SLE activity did not increase costimulatory molecule expression or cytokine production after ODN-CpG stimulation. APCs from patients with SLE, regardless of disease activity, displayed higher percentage of TLR9+ cells, as well as increased expression of TLR9, compared to healthy controls. Results suggest that the B cell response to ODN-CpG correlates with the SLE activity, independently of TLR9 expression, indicating that alterations in B cell response in severe activity SLE may be caused by events down-stream to TLR9.
Lupus 2009 Jul
PMID:Response to ODN-CpG by B Cells from patients with systemic lupus erythematosus correlates with disease activity. 1950 68

Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR(-/-) mice. Numbers of activated CD40(high) plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR(-/-) mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR(-/-) spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR(-/-) DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR(-/-) DC produced less IL-12p40/70 and TNF-alpha than did NZM DC. The limited IFNAR(-/-) DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4(+) T cells and CD19(+) B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.
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PMID:Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. 1981 95


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