Abstract
ObjectivesAbatacept acts as a competitive inhibitor of the CD28/(CD80/86) costimulation signal required for T cell activation. Mechanisms of action of abatacept have not been fully investigated. The objective of this study was to provide detailed insight into the mode of action of Abatacept based on gene expression data.MethodsIn this ancillary study from the APPRAISE trial, we investigated the global molecular effects of Abatacept in whole blood samples collected prospectively in biologic naive rheumatoid arthritis patients (n = 19) at baseline and 6 months after the initiation of Abatacept therapy concomitant with methotrexate. Whole human genome microarrays (4x44K) were performed on both baseline and 6-month samples from responders and non-responders patients categorized according to EULAR criteria. T-test with Benjamini-Hochberg correction was performed to identify significant gene expression changes. Gene Ontology and Single Experiment Analysis tools allowed us to highlight specific biological mechanisms involved in methotrexate/Abatacept.ResultsIn methotrexate/Abatacept responders, 672 genes were significantly (q<0.05) dysregulated at 6 months compared to baseline. Correlation analysis highlighted 19 genes whose dysregulations were significantly associated with disease activity variation (p<0.05) and whose functions were associated with proliferation, apoptosis of cells and mitochondrial metabolism, suggesting a restoration of oxidative signaling. The other 653 gene expression changes were relative to direct or indirect effects of methotrexate/Abatacept treatment and were significantly (p<0.005) involved in pathways relative to mRNA processing, proteasome, angiogenesis, apoptosis and TCR signaling. This study highlights new mechanisms of action of methotrexate/Abatacept and may provide new therapeutic targets to prevent autoimmunity in rheumatoid arthritis.
Highlights
Abatacept (ABA) is indicated for the treatment of adult patients with moderately to severely active RA
Correlation analysis highlighted 19 genes whose dysregulations were significantly associated with disease activity variation (p
From the APPRAISE trial, 19 RA patients were selected among R (n = 14) and NR (n = 5) treated by MTX/ABA according to EULAR response criteria
Summary
Abatacept (ABA) is indicated for the treatment of adult patients with moderately to severely active RA. T cells are activated by the engagement of the T cell receptor (TCR) and the interaction of costimulatory molecules, such as CD80/CD86 on antigen presenting cells (APC), with CD28 on T cells. Activated T cells express T-lymphocyte antigen-4 (CTLA-4), which binds both costimulatory molecules CD80 and CD86, but in contrast to CD28 binding, delivers anti-proliferative signals that downregulate T cell activation [1,2,3]. CD80 and CD86 appear to present dual functions within the immune system: activation signals by their interaction with CD28 as well as inhibition signals by their interaction with CTLA-4. We sought to understand how ABA can act on both APC and T cells when ABA interacts with CD80/CD86
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
