AB0529 Rituximab therapy monitoring by mtor, autophagy-related ULK1, caspase 3, CDK-inhibitor P21, TNF alpha, and osteoclast-specific cathepsin K and gelatinase MMP-9 gene expression in the peripheral blood of rheumatoid arthritis patients

2013 ◽  
Vol 71 (Suppl 3) ◽  
pp. 668.9-668 ◽  
Author(s):  
E.V. Tchetina ◽  
K.H. Kuzikyants ◽  
A.Y. Devyataikina ◽  
G.V. Lukina ◽  
E.L. Nasonov
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Caspase 3 ◽  
Therapy Monitoring ◽  
Cathepsin K ◽  
Tnf Alpha ◽  
Cdk Inhibitor

scholarly journals Rituximab Downregulates Gene Expression Associated with Cell Proliferation, Survival, and Proteolysis in the Peripheral Blood from Rheumatoid Arthritis Patients: A Link between High Baseline Autophagy-Related ULK1 Expression and Improved Pain Control

Arthritis ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Elena V. Tchetina ◽  
Anastasya N. Pivanova ◽  
Galina A. Markova ◽  
Galina V. Lukina ◽  
Elena N. Aleksandrova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood ◽  
Healthy Subjects ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Bone Erosion ◽  
Cathepsin K ◽  
Joint Space ◽  
High Baseline ◽  
Cell Counts

Objective. To clarify molecular mechanisms for the response to rituximab in a longitudinal study. Methods. Peripheral blood from 16 RA patients treated with rituximab for a single treatment course and 26 healthy controls, blood and knee articular cartilages from 18 patients with long-standing RA, and cartilages from 14 healthy subjects were examined. Clinical response was assessed using ESR, ACPA, CRP, RF, DAS28 levels, CD19+ B-cell counts, bone erosion, and joint space narrowing scores. Protein expression in PBMCs was quantified using ELISA. Gene expression was performed with quantitative real-time PCR. Results. A decrease (p<0.05) in DAS28, ESR, and CRP values after rituximab treatment was associated with the downregulation of MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression in the peripheral blood to levels found in healthy subjects. MMP-9 expression remained significantly higher compared to controls although decreased (p<0.05) versus baseline. A negative correlation between baseline ULK1 gene expression and the number of tender joints at the end of follow-up was observed. Conclusions. The response to rituximab was associated with decreased MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression compared to healthy subjects. Residual increased expression in MMP-9, IFNα, and COX2 might account for remaining inflammation and pain. High baseline ULK1 gene expression indicates a good response in respect to pain.

scholarly journals Rheumatoid Factor Positivity Is Associated with Increased Joint Destruction and Upregulation ofMatrix Metalloproteinase 9andCathepsin KGene Expression in the Peripheral Blood in Rheumatoid Arthritic Patients Treated with Methotrexate

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Elena V. Tchetina ◽  
Natalia V. Demidova ◽  
Dmitry E. Karateev ◽  
Eugeny L. Nasonov
Keyword(s):  
Gene Expression ◽  
Rheumatoid Factor ◽  
Peripheral Blood ◽  
Caspase 3 ◽  
Joint Destruction ◽  
Previous History ◽  
Cathepsin K ◽  
Tissue Destruction ◽  
Rheumatoid Arthritic

We evaluated changes in gene expression ofmTOR,p21,caspase-3,ULK1,TNFα, matrix metalloproteinase(MMP)-9, andcathepsin Kin the whole blood of rheumatoid arthritic (RA) patients treated with methotrexate (MTX) in relation to their rheumatoid factor status, clinical, immunological, and radiological parameters, and therapeutic response after a 24-month follow-up. The study group consisted of 35 control subjects and 33 RA patients without previous history of MTX treatment. Gene expression was measured using real-time RT-PCR. Decreased disease activity in patients at the end of the study was associated with significant downregulation ofTNFαexpression. Downregulation ofmTORwas observed in seronegative patients, while no significant changes in the expression ofp21,ULK1, orcaspase-3were noted in any RA patients at the end of the study. The increase in erosion numbers observed in the seropositive patients at the end of the follow-up was accompanied by upregulation ofMMP-9andcathepsin K, while seronegative patients demonstrated an absence of significant changes inMMP-9andcathepsin Kexpression and no increase in the erosion score. Our results suggest that increased expression ofMMP-9andcathepsin Kgenes in the peripheral blood might indicate higher bone tissue destruction activity in RA patients treated with methotrexate. The clinical study registration number is 0120.0810610.

scholarly journals Anti-Rheumatic Effect of Antisense Oligonucleotide Cytos-11 Targeting TNF-α Expression

2021 ◽  
Vol 22 (3) ◽  
pp. 1022
Author(s):  
Tatyana P. Makalish ◽  
Ilya O. Golovkin ◽  
Volodymyr V. Oberemok ◽  
Kateryna V. Laikova ◽  
Zenure Z. Temirova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Rat Model ◽  
Peripheral Blood ◽  
Antisense Oligonucleotide ◽  
Joint Inflammation ◽  
Blood Concentrations ◽  
Tnf Α ◽  
Effective Drugs ◽  
First Time

The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund’s adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.

scholarly journals Peripheral Blood Gene Expression and IgG Glycosylation Profiles as Markers of Tocilizumab Treatment in Rheumatoid Arthritis

2012 ◽  
Vol 39 (5) ◽  
pp. 916-928 ◽  
Author(s):  
BERTALAN MESKO ◽  
SZILARD POLISKA ◽  
SZILVIA SZAMOSI ◽  
ZOLTAN SZEKANECZ ◽  
JANOS PODANI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Multiple Testing ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Response To Treatment ◽  
Peripheral Blood Mononuclear ◽  
Gene Sets

Objective.Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has recently been approved as a biological therapy for rheumatoid arthritis (RA) and other diseases. It is not known if there are characteristic changes in gene expression and immunoglobulin G glycosylation during therapy or in response to treatment.Methods.Global gene expression profiles from peripheral blood mononuclear cells of 13 patients with RA and active disease at Week 0 (baseline) and Week 4 following treatment were obtained together with clinical measures, serum cytokine levels using ELISA, and the degree of galactosylation of the IgG N-glycan chains. Gene sets separating responders and nonresponders were tested using canonical variates analysis. This approach also revealed important gene groups and pathways that differentiate responders from nonresponders.Results.Fifty-nine genes showed significant differences between baseline and Week 4 and thus correlated with treatment. Significantly, 4 genes determined responders after correction for multiple testing. Ten of the 12 genes with the most significant changes were validated using real-time quantitative polymerase chain reaction. An increase in the terminal galactose content of N-linked glycans of IgG was observed in responders versus nonresponders, as well as in treated samples versus samples obtained at baseline.Conclusion.As a preliminary report, gene expression changes as a result of tocilizumab therapy in RA were examined, and gene sets discriminating between responders and nonresponders were found and validated. A significant increase in the degree of galactosylation of IgG N-glycans in patients with RA treated with tocilizumab was documented.

scholarly journals Peripheral blood gene expression profiling in rheumatoid arthritis

2005 ◽  
Vol 6 (5) ◽  
pp. 388-397 ◽  
Author(s):  
F M Batliwalla ◽  
E C Baechler ◽  
X Xiao ◽  
W Li ◽  
S Balasubramanian ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Gene Expression Profiling ◽  
Peripheral Blood ◽  
Expression Profiling ◽  
Blood Gene Expression ◽  
Peripheral Blood Gene Expression

Kinase Inhibitors Reduce TNF-Alpha Over-Production in Monocytes From Fanconi Anemia Group A Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2409-2409
Author(s):  
Enrico Cappelli ◽  
Johanna Svahn ◽  
Praveen Anur ◽  
Fabio Corsolini ◽  
Piero Farruggia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fanconi Anemia ◽  
Peripheral Blood ◽  
Kinase Inhibitors ◽  
Bone Marrow Failure ◽  
Mononuclear Phagocytes ◽  
Tnf Alpha ◽  
Regulatory Pathways ◽  
Alpha Production ◽  
Alpha Gene

Abstract Abstract 2409 Fanconi Anemia (FA) is a chromosomal instability syndrome with hypersensitivity to alkylating agents as principal diagnostic feature. Many laboratories have demonstrated the involvement of FA proteins in DNA repair mechanisms. Recent work has also demonstrated other functions of some FA proteins suggesting that they play alternative roles in other regulatory pathways, particularly those that influence hematopoiesis. Eighty percent of FA patients develop bone marrow failure with a high incidence of evolution in myelodysplasia and/or acute leukemia. Each of these abnormalities has been related to TNF-alpha hypersensitivity in the stem and progenitor cell pools and the toll-like receptor dependent overproduction of TNF-alpha by FA macrophages. The TNF-hypersensitive phenotype involves at least two kinases, PKR and ASK1, each of which is hyperactivated in FA cells and induce apoptotic responses both in ground state and after TNF-alpha and IFN-gamma stimulation. Recent evidence showed that R848 (a TLR8 ligand) and endotoxin (LPS, a TLR4 ligand)-induced TNF-alpha gene expression in Fancc-deficient mononuclear phagocytes cells is inhibited by kinase inhibitors dasatinib and BIRB796 We sought to evaluate the activity of these agents in primary mononuclear phagocytes obtained from children with FA-A. Objectives: To determine whether primary monocytes from the peripheral blood of FANCA-deficient patients: (a) exhibit the TNF-overproduction phenotype in response to LPS and the TLR8 ligand R848, and (b) respond to dasatinib and BIRB796 by suppressing TNF-production. Methods: Six FA patients with mild to severe marrow failure on no treatment were included in this study. Healthy subjects were recruited as normal controls that were run in parallel in each case. CD14+ monocytes freshly isolated from peripheral blood were cultured for 24 hours with LPS and R848 with or without dasatinib or BIRB796. Supernatant media were collected and frozen at −80 degrees. After thawing the samples, TNF-alpha content was quantified by ELISA. Results: Baseline TNF-alpha concentration (without any TLR stimulation) was higher in FA patients than control. After LPS or R848 stimulation FA-A monocytes produced substantially more TNF-alpha than did the control samples. Both dasatinib and BIRB796 suppressed TLR-induced (both LPS and R848) TNF-alpha production. Specifically, with R848 as the agonist, BIRB 769 suppressed TNF-alpha production by 60% and dasatinib by 42%. Both inhibitors were even more potent in suppressing LPS induced TNF-alpha expression as both reduced TNF-alpha by 75%. In the absence of TLR stimulation, the presence of BIRB or dasatinib in culture reduced TNF-alpha by >50% compared to baseline in patient samples. The inhibitory effect of kinase inhibitors was observed also in the normal control. Conclusions: These findings: (a) demonstrate for the first time that TLR-induced TNF-alpha gene expression in primary FANCA deficient mononuclear phagocytes is aberrantly regulated and (b) that in FANCA-deficient macrophages the TNF-alpha overproduction phenotype can be controlled by therapeutically achievable doses of BIRB796 and dasatinib. In addition (c), since both agents function in large part to suppress p38 MAPK activation future, our data point to the biochemical roles played by FANCA in modulating upstream pathways that govern p38 activation. Moreover (d), given that in FA patients, TNF hypersensitive stem cells are over-exposed to TNF-alpha, particularly during inflammatory events and that exposure to TNF was shown not only to suppress hematopoiesis in FA but also to favor the emergence of neoplastic clones, these results point to these two agents as potential candidates for preclinical trials seeking to enhance hematopoiesis and suppress clonal evolution. Disclosures: No relevant conflicts of interest to declare.

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