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JAK inhibitor ameliorate autoimmunity and nephritis in lupus prone mice

ABSTRACT: 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, naÃ¯ve 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.

ORGANISM(S): Mus musculus

SUBMITTER: Keigo Ikeda

PROVIDER: E-GEOD-78825 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation.

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

Expression data from lupus NZB/W and NZW/BXSB mouse prenephritic kidneys

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Stretch-Enhancers Delineate Disease-Associated Regulatory Nodes in T Cells

Project description:T Cell stretch-enhancers are vulnerable to Jak inhibitor tofacitinib Treatment of T cells with the Janus kinase (JAK) inhibitor, tofacitinib, disproportionately altered the expression of RA risk genes with stretech-enhancer (SE) structures.

2015-02-18 | E-GEOD-60482 | biostudies-arrayexpress

Estrogen signaling through Estrogen Receptor ⍺ alters lipid metabolism and promotes glomerulonephritis

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Targeting neddylation is a novel therapeutic strategy for lupus by reconstructing double negative T cell homeostasis

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2024-01-26 | PXD045686 | Pride

Genome-wide peripheral blood transcriptome analysis of Arab female Lupus and Lupus nephritis

Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (p≤0.05,SI>or≤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with p≤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN.

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