Project description:The objective of this study was to identify response-specific gene expression fluctuations in methotrexate /abatacept (Aba) treated rheumatoid arthritis patients : responders (R) VS no-responders (NR). Nineteen RA patients were received Abatacept. The drug efficacy was evaluated with the DAS28 score after 6 months of treatment according to the EULAR response criteria. Among 19 Aba RA patients, 14 were R and 5 were classified as NR. A blood sample was carried out in patients both at baseline (just before the first injection of ABA) and at 6 months in PaxGene tubes.
Project description:The objective of this study was to identify specific gene expression profiles able to predict the response of rheumatoid arthritis patients treated with methotrexate /abatacept (Aba). Thirty six RA patients were received Abatacept. The drug efficacy was evaluated with the DAS28 score after 6 months of treatment according to the EULAR response criteria. Among 36 Aba RA patients, 17 were responders and 19 were classified as no-responders. A blood sample was carried out in patients just before the first injection of treatment in PaxGene tubes. Two color experiments : patient(Cy5)/Control pool (Cy3).
Project description:The objective of this study was to identify specific gene expression profiles able to predict the response of rheumatoid arthritis patients treated with methotrexate /abatacept (Aba). Thirty six RA patients were received Abatacept. The drug efficacy was evaluated with the DAS28 score after 6 months of treatment according to the EULAR response criteria. Among 36 Aba RA patients, 17 were responders and 19 were classified as no-responders. A blood sample was carried out in patients just before the first injection of treatment in PaxGene tubes.
Project description:The efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic gene expression subset would show the most significant clinical improvement. 84 participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-seq was performed on 233 skin paired biopsies at baseline, 3- and 6-months. Improvement was defined as a 5 point or >20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subset (inflammatory, fibroproliferative, or normal-like). In the abatacept arm, change in mRSS was most pronounced for the inflammatory (p<0.001) and normal-like (p=0.03) subsets relative to placebo. Participants on placebo remained in their molecular subset while inflammatory participants treated with abatacept moved toward normal-like. The CD28 costimulation pathway decreased in patients that improved on abatacept (FDR=5.88x10-4) and was specific to the inflammatory subset (FDR=0%). Patients in the inflammatory subset had elevation of the CD28 costimulation pathway at baseline relative to fibroproliferative (p = 0.0026) and normal-like (p=0.0001) participants. There was a correlation between improved ΔmRSS and baseline expression of the CD28 costimulation pathway (R=-0.62, p=0.02). This study provides an example of precision medicine in SSc clinical trials.
Project description:To explore markers which predict the efficacy of abatacept in rheumatoid arthritis, peripheral blood mononuclear cells were obtained before abatacept treatment.
Project description:Abatacept is a recombinant CTLA-4 moleculed fused to a mutated human IgG molecule, which is clinically used in rheumatoid arthritis by inhibiting CD28-costimulation. This study aimed to inverstigate the ability of abatacept -mediated costimulation blockade to induce antigen-specific tolerance during primary immune responses. This is important as some studies have suggested that costimulation blockade can lead to CD4+ T cell anergy which could be beneficial for early therapy of autoimmune diseases such as rheumatoid arthritis. In addition we also investigated the effect that abatacept has on CD11c+ antigen presenting cells. This is important as costimulation blocakde can affect the biderectional interaction between CD4+ T cells and CD11c+ cells influencing the immunological outcome. We used microarrays to identify if abatacept treatment leads to antigen specific anergy using transgenic animals and models of priming and oral tolerance that established a synchronised monoclonal response. In addition this magnified the effect on the CD11c+ antigen presenting cells. This study included 5 experimental groups. DO11.10 RAG2-/- mice have CD4+ T cells specific for the ovalbumin (OVA) peptide OVA323-339. These mice were immunised with CFA/OVA s.c. (primed group) or tolerised by feeding with OVA (50mg/kg) in the drinking water. CD4+ cells were isolated 10 days post immunisation from draining lymph nodes (LNs) of unimmunised (pooled LNs and Spleen), orally tolerised (mesenteric LNs), primed (axillary LNs), primed treated with control IgG (axillary LNs) and primed treated with abatacept (axillary LNs). For CD11c+ cells cells were isolated by pooled secondary lymphoid organs (LNs and spleen).
Project description:Abatacept is a recombinant CTLA-4 moleculed fused to a mutated human IgG molecule, which is clinically used in rheumatoid arthritis by inhibiting CD28-costimulation. This study aimed to inverstigate the ability of abatacept -mediated costimulation blockade to induce antigen-specific tolerance during primary immune responses. This is important as some studies have suggested that costimulation blockade can lead to CD4+ T cell anergy which could be beneficial for early therapy of autoimmune diseases such as rheumatoid arthritis. In addition we also investigated the effect that abatacept has on CD11c+ antigen presenting cells. This is important as costimulation blocakde can affect the biderectional interaction between CD4+ T cells and CD11c+ cells influencing the immunological outcome. We used microarrays to identify if abatacept treatment leads to antigen specific anergy using transgenic animals and models of priming and oral tolerance that established a synchronised monoclonal response. In addition this magnified the effect on the CD11c+ antigen presenting cells.
Project description:RA patients (according to ACR/EULAR 2010 criteria) who started abatacept due to high disease activity (DAS28>5.1), were recruited to perform immunological studies at baseline, 3 and 6 months of therapy. Peripheral blood mononuclear cells (PBMCs) were isolated and immune cell populations were characterized using flow cytometry. Proteomic analysis was performed on baseline sera.
Project description:Intent of this experiment is to define the baseline transcriptome of the synovium obtained from rheumatoid arthritis patients prior to initiation of DMARD (Disease-modifying antirheumatic drug) therapy and compare it with the synovial transcriptome of rheumatoid arthritis patients with an established disease profile.