Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice.

ABSTRACT: The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-γ-positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-γ and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells.

SUBMITTER: Look M

PROVIDER: S-EPMC3613921 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus.

Project description:IntroductionClinical trials revealed a high efficacy of mycophenolate mofetil (MMF)in inducing and maintaining remission in patients with class III-V-lupus nephritis. Also extrarenal manifestations respond to MMF treatment. However, few attempts have been undertaken to delineate its mechanism of action in systemic lupus erythematosus (SLE) a disease characterized by enhanced B cell activation.MethodsClinical and paraclinical parameters of 107 patients with SLE were recorded consecutively and analyzed retrospectively. Patients were divided into treatment groups (MMF: n=39, azathioprine (AZA) n=30 and controls without immunosuppressive therapy n=38). To further delineate the effect of mycophenolic acid (MPA) on naive and memory B cells in vitro assays were performed.ResultsAlthough patients taking AZA flared more frequently than patients on MMF or controls, the analysis of clinical parameters did not reveal significant differences.However, profound differences in paraclinical parameters were found. B cell frequencies and numbers were significantly higher in patients taking MMF compared to those on AZA but lower numbers and frequencies of plasmablasts were detected compared to AZA-treated patients or controls. Notably, MMF treatment was associated with a significantly higher frequency and number of transitional B cells as well as naive B cells compared to AZA treatment. Differences in T cell subsets were not significant. MPA abrogated in vitro proliferation of purified B cells completely but had only moderate impact on B cell survival.ConclusionsThe thorough inhibition of B cell activation and plasma cell formation by MMF might explain the favorable outcomes of previous clinical trials in patients with SLE, since enhanced B cell proliferation is a hallmark of this disease.

| S-EPMC4060361 | biostudies-literature

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus.

Project description:The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4-CD8- T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

| S-EPMC8073120 | biostudies-literature

Deficient leptin signaling ameliorates systemic lupus erythematosus lesions in MRL/Mp-Fas lpr mice.

Project description:Leptin is secreted by adipocytes, the placenta, and the stomach. It not only controls appetite through leptin receptors in the hypothalamus, it also regulates immunity. In the current study, we produced leptin-deficient MRL/Mp-Fas(lpr) mice to investigate the potential role of leptin in autoimmunity. C57BL/6J-ob/ob mice were backcrossed with MRL/Mp-Fas(lpr) mice, which develop human systemic lupus erythematosus (SLE)-like lesions. The effects of leptin deficiency on various SLE-like manifestations were investigated in MRL/Mp-Fas(lpr) mice. The regulatory T cell population in the spleen was analyzed by flow cytometry, and the effects of leptin on regulatory T cells and Th17 cells were evaluated in vitro. Compared with leptin-producing MRL/Mp-Fas(lpr) mice, leptin-deficient MRL/Mp-Fas(lpr) mice showed less marked splenomegaly and a particularly low population of CD3(+)CD4(-)CD8(-)B220(+) T cells (lpr cells). Their serum concentrations of Abs to dsDNA were lower, and renal histological changes at age 20 wk were ameliorated. Regulatory T cells were increased in the spleens of leptin-deficient MRL/Mp-Fas(lpr) mice. Leptin suppressed regulatory T cells and enhanced Th17 cells in vitro. In conclusion, blockade of leptin signaling may be of therapeutic benefit in patients with SLE and other autoimmune diseases.

| S-EPMC3897175 | biostudies-other

Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus.

Project description:Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain-containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-? and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-? and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients.

| S-EPMC4887187 | biostudies-literature

Systemic lupus erythematosus

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-03 | E-GEOD-46923 | biostudies-arrayexpress

Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus.

Project description:BACKGROUND:Plasmacytoid DCs (pDC) produce large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis. BIIB059 is a humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. A first-in-human study was conducted to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects of single BIIB059 doses in healthy volunteers (HV) and patients with SLE with active cutaneous disease as well as proof of biological activity and preliminary clinical response in the SLE cohort. METHODS:A randomized, double-blind, placebo-controlled clinical trial was conducted in HV (n = 54) and patients with SLE (n = 12). All subjects were monitored for adverse events. Serum BIIB059 concentrations, BDCA2 levels on pDCs, and IFN-responsive biomarkers in whole blood and skin biopsies were measured. Skin disease activity was determined using the Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A). RESULTS:Single doses of BIIB059 were associated with favorable safety and PK profiles. BIIB059 administration led to BDCA2 internalization on pDCs, which correlated with circulating BIIB059 levels. BIIB059 administration in patients with SLE decreased expression of IFN response genes in blood, normalized MxA expression, reduced immune infiltrates in skin lesions, and decreased CLASI-A score. CONCLUSIONS:Single doses of BIIB059 were associated with favorable safety and PK/PD profiles and robust target engagement and biological activity, supporting further development of BIIB059 in SLE. The data suggest that targeting pDCs may be beneficial for patients with SLE, especially those with cutaneous manifestations. TRIAL REGISTRATION:ClinicalTrials.gov NCT02106897. FUNDING:Biogen Inc.

| S-EPMC6391094 | biostudies-literature

Systemic lupus erythematosus

Project description:This SuperSeries is composed of the SubSeries listed below.

2014-06-03 | GSE46923 | GEO

Systemic lupus erythematosus.

Project description: Not available

| S-EPMC1440614 | biostudies-literature

Systemic lupus erythematosus.

Project description: Not available

| S-EPMC2048842 | biostudies-literature

Systemic Lupus Erythematosus Delivery Outcomes Are Unchanged Across Three Decades.

Project description:ObjectiveUsing a large, de-identified electronic health record database with over 3.2 million patients, we aimed to identify trends of systemic lupus erythematosus (SLE) medication use during pregnancy and birth outcomes from 1989 to 2020.MethodsUsing a previously validated algorithm for SLE deliveries, we identified 255 pregnancies in patients with SLE and 604 pregnancies in controls with no known autoimmune diseases. We examined demographics, medications, SLE comorbidities, and maternal and fetal outcomes in SLE and control deliveries.ResultsCompared with control deliveries, SLE deliveries were more likely to be complicated by preterm delivery (odds ratio [OR]: 6.71; 95% confidence interval [CI]: 4.31-10.55; P < 0.001) and preeclampsia (OR: 3.22; 95% CI: 1.83-5.66; P < 0.001) after adjusting for age at delivery, race, and parity. In a longitudinal analysis, medication use during SLE pregnancies remained relatively stable, with some increased use of hydroxychloroquine over time but no increase in aspirin use. For SLE deliveries, preterm delivery and preeclampsia rates remained stable.ConclusionWe observed rates of preeclampsia and preterm delivery in SLE that were five times higher than the general population and higher compared with other prospective SLE cohorts. Furthermore, we did not observe improved outcomes over time with preeclampsia and preterm delivery. Despite increasing evidence for universal use of hydroxychloroquine and aspirin, we did not observe substantially higher use of these medications over time, particularly for aspirin. Our results demonstrate the continued need to prioritize educational and implementation efforts to improve adverse pregnancy outcomes in SLE.

| S-EPMC9374054 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data