Daratumumab in systemic lupus erythematosus: a phase 2 trial
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE294789 | GEO | 2025/12/13
REPOSITORIES: GEO
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Project description:Rationale: Elevated numbers of antibody secreting cells (ASCs) and anti-dsDNA antibodies are found in nasal polyp (NP) tissue. Tissue anti-dsDNA IgG prospectively predicts recurrent NP, but the characteristics of the source ASCs are unknown. Objectives: To investigate whether NP B cells expressing the extrafollicular marker EBI2 have increased propensity for autoantibody production and to evaluate the molecular characteristics of NP ASCs. Findings: NPs (n=8) showed increased frequencies of anti-dsDNA IgG and total IgG ASCs (34- and 9-fold, respectively, both p<0.0001) compared to tonsils (n=10), with more pronounced differences among EBI2+ cells. In NPs, EBI2+ cells were frequently double-negative (IgD-CD27-) and ASCs (36.3% and 19.5%, respectively). ScRNA-seq analysis of tonsils and NPs (both n=5) revealed substantial differences in B lineage composition: ASCs (1.2% vs 44.1%), germinal center (23.1% vs 0.2%), proliferative (12.6% vs 3.0%), and non-ASCs (63.1% vs 52.7%), respectively. NPs exhibited higher expression (>2-fold) of specific isotypes (IGHE, IGHA1, IGHA2, and IGHG4), and mature plasma genes including SDC1 and XBP1 than tonsils. GO biological processes indicated upregulated NF-κB and downregulated apoptosis pathways in NP ASCs. Conclusions: NP EBI2+ ASCs secreted increased total and anti-dsDNA IgG compared to those from tonsils and had molecular features of mature plasma cell differentiation.
2024-09-10 | GSE270953 | GEO
Project description:We performed a high-resolution analysis of the biological characteristics of plasma DNA in systemic lupus erythematosus (SLE) patients using massively parallel genomic and methylomic sequencing. A number of plasma DNA abnormalities were found. First, aberrations in measured genomic representations (MGRs) were identified in the plasma DNA of SLE patients. The extent of the aberrations in MGRs correlated with anti-double–stranded DNA (anti-dsDNA) antibody level. Second, the plasma DNA of active SLE patients exhibited skewed molecular size-distribution profiles with a significantly increased proportion of short DNA fragments. The extent of plasma DNA shortening in SLE patients correlated with the SLE disease activity index (SLEDAI) and anti-dsDNA antibody level. Third, the plasma DNA of active SLE patients showed decreased methylation densities. The extent of hypomethylation correlated with SLEDAI and anti-dsDNA antibody level. To explore the impact of anti-dsDNA antibody on plasma DNA in SLE, a column-based protein G capture approach was used to fractionate the IgG-bound and non–IgG-bound DNA in plasma. Compared with healthy individuals, SLE patients had higher concentrations of IgG-bound DNA in plasma. More IgG binding occurs at genomic locations showing increased MGRs. Furthermore, the IgG-bound plasma DNA was shorter in size and more hypomethylated than the non–IgG-bound plasma DNA. These observations have enhanced our understanding of the spectrum of plasma DNA aberrations in SLE and may provide new molecular markers for SLE. Our results also suggest that caution should be exercised when interpreting plasma DNA-based noninvasive prenatal testing and cancer testing conducted for SLE patients.
| EGAS00001000962 | EGA
Project description:Background: Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ-lpr/lpr (MRL/lpr) mice with severe disease activity. Methods: Female MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate-buffered saline (PBS) (n = 13), Bz (750 μg/kg twice weekly) (n = 12), and cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 15). Cellular subsets, serum immunoglobulin, anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10 and 14 weeks-Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice. Results: The anti-dsDNA antibody levels were significantly higher in 14- than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz- and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14- than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF-α levels were significantly more elevated in 14- than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins and calreticulin, were specifically upregulated in spleens of Bz- but not Cyc-treated mice. Conclusions: In spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased pro-inflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE.
2017-02-10 | GSE94750 | GEO
Project description:We previously reported that JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE through analyzing the difference of gene expression in peripheral blood CD3+ T cells obtained from SLE patients. Recently pan-JAK inhibitor (JAKi) tofacitinib (TOFA) were developed and successfully applied to patients with rheumatoid arthritis. Therefore, the application possibility of TOFA was investigated for the new therapeutic strategy of SLE. Anti-dsDNA antibody and proteinuria were decreased and glomerulo/interstitial nephritis were ameliorated in any TOFA administered SLE mice. In splenic CD4+ T cell analysis, naïve cells significantly increased and effector/memory cells decreased. TOFA with dexamethasone (DEXA) therapy showed tendency to indicate stronger inhibitory effect comparing with TOFA or DEXA monotherapy. The gene expression of Ifit3/IFIT3 that related with anti-viral IFN signaling pathway was significantly suppressed in both CD4+ from SLE mice and CD3+ T cells from SLE patients after treatment. Both TOFA monotherapy and dual therapy with DEXA could suppress nephritis and modify immunological function in SLE mice with different genetic background. IFN signaling pathway was supposed to be important for the functional mechanism of TOFA to improve the disease condition. TOFA may contribute to the development of a new therapeutic strategy for SLE. The gene expression analysis was compared among tofacitinib, tofacitinib+dexamethsone, dexamethsone and non-treated control groups and extracted TOFA specific decreased genes in NZBWF1 mice.
2016-03-03 | E-GEOD-78825 | biostudies-arrayexpress
Project description:We previously reported that JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE through analyzing the difference of gene expression in peripheral blood CD3+ T cells obtained from SLE patients. Recently pan-JAK inhibitor (JAKi) tofacitinib (TOFA) were developed and successfully applied to patients with rheumatoid arthritis. Therefore, the application possibility of TOFA was investigated for the new therapeutic strategy of SLE. Anti-dsDNA antibody and proteinuria were decreased and glomerulo/interstitial nephritis were ameliorated in any TOFA administered SLE mice. In splenic CD4+ T cell analysis, naïve cells significantly increased and effector/memory cells decreased. TOFA with dexamethasone (DEXA) therapy showed tendency to indicate stronger inhibitory effect comparing with TOFA or DEXA monotherapy. The gene expression of Ifit3/IFIT3 that related with anti-viral IFN signaling pathway was significantly suppressed in both CD4+ from SLE mice and CD3+ T cells from SLE patients after treatment. Both TOFA monotherapy and dual therapy with DEXA could suppress nephritis and modify immunological function in SLE mice with different genetic background. IFN signaling pathway was supposed to be important for the functional mechanism of TOFA to improve the disease condition. TOFA may contribute to the development of a new therapeutic strategy for SLE.
2016-03-03 | GSE78825 | GEO
Project description:Single cell transcriptome and TCR sequencing of FACS-sorted memory T cells in one patient under treatment with the anti CD38-antibody Daratumumab. The patient received Daratumumab at days 0, 7, 14 and 21. Analyses were performed on day 0, 41 and 74.
2020-09-11 | GSE153765 | GEO
Project description:We previously reported the establishment of a rabbit (Oryctolagus cuniculus) model of Systemic Lupus Erythematosus (SLE) in which peptide immunization led to lupus-like autoantibody production including anti-Sm, -RNP, -SS-A, -SS-B and -dsDNA. Some neurological symptoms in form of seizures and nystagmus were observed. The animals used in the previous and in the present study were from a National Institute of Allergy and Infectious Diseases colony of rabbits that were pedigreed, immunoglobulin allotype-defined but not inbred. Their genetic heterogeneity may correspond to that found among patients of a given ethnicity. We extended the information about this rabbit model of SLE by microarray based expression profiling. We first demonstrated that human expression arrays could be used with rabbit RNA to yield information on molecular pathways. We then designed a study evaluating gene expression profiles in 8 groups of control and SLE rabbits (46 rabbits in total). Genes significantly upregulated in SLE rabbits were associated with NK cytotoxicity, antigen presentation, leukocyte migration, cytokine activity, protein kinases, RNA spliceosomal ribonucleoproteins, intracellular signaling cascades, and glutamate receptor activity. These results link increased immune activation with up-regulation of components associated with neurological and anti-RNP responses, demonstrating the utility of the rabbit SLE model to uncover biological pathways related to SLE-induced clinical symptoms, including Neuropsychiatric Lupus. Our finding of distinct gene expression patterns in rabbits that made anti-dsDNA compared to those that only made other anti-nuclear antibodies should be further investigated in subsets of SLE patients with different autoantibody profiles.
2010-07-23 | GSE23076 | GEO
Project description:Natural killer (NK) cells support the anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC) in multiple myeloma (MM). However, the different roles of heterogeneous NK cell subpopulations have not been elucidated in MM. Here, we delineate memory-like NK cells in the bone marrow (BM) of newly diagnosed MM (NDMM) patients using single-cell RNA sequencing, and further characterize their distinct immunophenotypic features and functions by multicolor flow cytometry. Memory-like NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared to conventional NK cells. The composition of memory-like NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in NDMM patients. Unlike conventional NK cells, sorted memory-like NK cells from the BM of NDMM patients exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab. Our findings indicate that memory-like NK cells are an important mediator of daratumumab-dependent effector functions in MM and support direct future efforts to better predict and improve the clinical efficacy of therapeutic antibodies by selectively employing memory-like NK cells.
2021-08-01 | GSE155795 | GEO
Project description:Objective: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Methods: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in TempusTM tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoStringTM. Results: At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predictor of future time to flare, independent of anti-double stranded DNA antibody (dsDNA), C3 and C4 levels, and overall disease activity. PD changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin (Ig) genes, and were consistent with other PD-induced changes including dsDNA, C3, and Ig levels. Conclusions: SLE patients demonstrated elevated expression of an IRG signature, detected in 75% of the patients at baseline in ILLUMINATE-1 and -2. There was substantial heterogeneity of gene expression detected among individual patients and in gene networks. The interferon signature was an independent risk factor for future flares. PD changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
2016-10-25 | GSE88885 | GEO
Project description:Objective: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Methods: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in TempusTM tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoStringTM. Results: At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predictor of future time to flare, independent of anti-double stranded DNA antibody (dsDNA), C3 and C4 levels, and overall disease activity. PD changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin (Ig) genes, and were consistent with other PD-induced changes including dsDNA, C3, and Ig levels. Conclusions: SLE patients demonstrated elevated expression of an IRG signature, detected in 75% of the patients at baseline in ILLUMINATE-1 and -2. There was substantial heterogeneity of gene expression detected among individual patients and in gene networks. The interferon signature was an independent risk factor for future flares. PD changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
2016-10-25 | GSE88886 | GEO