scholarly journals Photopheresis efficacy in the treatment of rheumatoid arthritis: a pre-clinical proof of concept

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Céline Coppard ◽  
Francis Bonnefoy ◽  
Dalil Hannani ◽  
Françoise Gabert ◽  
Olivier Manches ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Cell ◽  
Unmet Need ◽  
Proof Of Concept ◽  
Therapeutic Approaches ◽  
Spleen Cells ◽  
New Therapeutic Approaches ◽  
Bovine Collagen ◽  
Treated Sample ◽  
Immune Cell Subsets

Abstract Background Despite major advances in rheumatoid arthritis outcome, not all patients achieve remission, and there is still an unmet need for new therapeutic approaches. This study aimed at evaluating in a pre-clinical murine model the efficacy of extracorporeal photopheresis (ECP) in the treatment of rheumatoid arthritis, and to provide a relevant study model for dissecting ECP mechanism of action in autoimmune diseases. Methods DBA/1 mice were immunized by subcutaneous injection of bovine collagen type II, in order to initiate the development of collagen-induced arthritis (CIA). Arthritic mice received 3 ECP treatments every other day, with psoralen + UVA-treated (PUVA) spleen cells obtained from arthritic mice. Arthritis score was measured, and immune cell subsets were monitored. Results ECP-treated mice recovered from arthritis as evidenced by a decreasing arthritic score over time. Significant decrease in the frequency of Th17 cells in the spleen of treated mice was observed. Interestingly, while PUVA-treated spleen cells from healthy mouse had no effect, PUVA-treated arthritic mouse derived-spleen cells were able to induce control of arthritis development. Conclusions Our results demonstrate that ECP can control arthritis in CIA-mice, and clarifies ECP mechanisms of action, showing ECP efficacy and Th17 decrease only when arthritogenic T cells are contained within the treated sample. These data represent a pre-clinical proof of concept supporting the use of ECP in the treatment of RA in Human.

scholarly journals New Therapeutic Approaches for the Treatment of Rheumatoid Arthritis may Rise from the Cholinergic Anti-Inflammatory Pathway and Antinociceptive Pathway

2010 ◽  
Vol 10 ◽  
pp. 2248-2253 ◽  
Author(s):  
Xiao Hua Pan ◽  
Jianxin Zhang ◽  
Xiaowei Yu ◽  
Ling Qin ◽  
Ligeng Kang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Therapeutic Approaches ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Drug Discovery And Development ◽  
New Therapeutic Approaches ◽  
Inflammatory Drugs ◽  
Disease Modifying ◽  
Anti Inflammatory ◽  
Current Stage

Due to the complex etiology of rheumatoid arthritis (RA), it is difficult to be completely cured at the current stage although many approaches have been applied in clinics, especially the wide application of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). New drug discovery and development via the recently discovered cholinergic anti-inflammatory and antinociceptive pathways should be promising. Based on the above, the nicotinic acetylcholine receptor agonists maintain the potential for the treatment of RA. Therefore, new therapeutic approaches may rise from these two newly discovered pathways. More preclinical experiments and clinical trials are required to confirm our viewpoint.

scholarly journals Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244187
Author(s):  
Jason Ptacek ◽  
Rachael E. Hawtin ◽  
Dongmei Sun ◽  
Brent Louie ◽  
Erik Evensen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Treatment Response ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Peripheral Blood Mononuclear ◽  
Immune Cell Subsets ◽  
Systems Immunology ◽  
Stat Signaling ◽  
Multiple Cell

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.

scholarly journals OP0128 DISTINCT FEATURES OF HLA-DR+ AND HLA-DR- PD-1HI CXCR5- T PERIPHERAL HELPER CELLS IN SEROPOSITIVE RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 84.2-84
Author(s):  
H. Yamada ◽  
T. Sasaki ◽  
K. Suzuki ◽  
M. Takeshita ◽  
S. Tanemura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Disease Activity ◽  
Plasma Cells ◽  
Immune Cell ◽  
Effector Memory ◽  
Chugai Pharmaceutical ◽  
Effector Memory T Cells ◽  
Hla Dr ◽  
Immune Cell Subsets

Background:PD-1hi CXCR5- T peripheral helper (Tph) cells are newly identified pathogenic CD4+ helper T cells in rheumatoid arthritis (RA). Since Tph cells have been emerged quite recently, the characteristics of Tph cells as a biomarker of RA are not fully understood.Objectives:The aim of the study is to evaluate how useful Tph cells in peripheral bloods are when compared to other immune cell subsets, and to clarify which Tph subset most accurately reflects the disease activity of RA.Methods:The RA patients who visited our rheumatology department between January 2000 and February 2017, and met the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria were included. We first assessed correlation with 40 immune cell subsets and the disease activity of RA. Next, the proportions of these immune cells were compared between RA and healthy controls (HCs). We also investigated the immune cell subsets which reflected the time course change of the disease activity after the methotrexate (MTX) treatment. The study protocol was approved by the ethics committee at Keio University School of Medicine.Results:Thirty-four seropositive RA, 12 seronegative RA and 34 HCs were included. The Immune cell subsets which showed correlation with DAS28-ESR (r> 0.2 or r> -0.2) were activated CD4 T cells (r= 0.31), HLA-DR+Th1 cells (r= 0.20), HLA-DR+Th1-17 cells (r= 0.25), Tfh1-17 cells (r= -0.25), HLA-DR+Tph cells (r= 0.22), CD3+CD8+naïve T cells (r= -0.25), CD3+CD8+effector memory T cells (r= -0.26), plasma cells (r= 0.40) and CD14++CD16+intermediate monocyte (r= 0.23). The proportions of HLA-DR+Th1 cells (2.3% vs. 5.7%), HLA-DR+Th1-17 cells (0.7% vs. 2.2%), Tfh1-17 cells (1.7% vs. 2.0%), HLA-DR+Tph cells (0.02% vs. 0.1%), CD3+CD8+effector memory T cells (16.6% vs 25.7%), plasma cells (0.04% vs. 0.17%) were statistically higher in the patients with RA compared to HCs. While the proportion of Tph cells showed weak correlation with DAS28-ESR (r= 0.18), that was extremely higher in RA (0.08% vs. 0.25%). Interestingly, when assessing the correlations with the disease activity in seropositive and seronegative RA separately, the proportions of Tph cells (r= 0.52) and HLA-DR+Tph cells (r= 0.50) were highly reflected in seropositive RA, but not in seronegative RA. Regarding the disease activity after the MTX treatment, the change of proportion of Tph cells between week 0 and 52 significantly reflected the change of DAS28-ESR (r= 0.75, p= 0.025), but not HLA-DR+Tph cells because of the non-specific reduction by the MTX treatment. Rather, HLA-DR-Tph cells significantly reflected the change of DAS28-ESR while receiving the MTX treatment (r= 0.76, p= 0.021).Conclusion:Tph cells and HLA-DR+Tph cells highly reflected the disease activity of seropositive RA. However, after the treatment, the proportion of HLA-DR+Tph cells decreased independent from the disease activity, and that of HLA-DR-Tph cells more accurately reflected the change of the disease activity during the treatment.References:[1]Rao DA, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542:110-114.Disclosure of Interests:Hiroki Yamada: None declared, Takanori Sasaki: None declared, Katsuya Suzuki: None declared, Masaru Takeshita: None declared, Shuhei Tanemura Employee of: I am employed by Mitsubishi Tanabe Pharma Corporation, Noriyasu Seki Employee of: I am employed by Mitsubishi Tanabe Pharma Corporation, Hideto Tsujimoto Employee of: I am employed by Mitsubishi Tanabe Pharma Corporation, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.

scholarly journals A Systems Immunology Approach Identifies Cytokine-Induced STAT Signaling Pathways Critical to Rheumatoid Arthritis Disease Activity and Treatment Response

2019 ◽  
Author(s):  
Jason Ptacek ◽  
Rachael E. Hawtin ◽  
Dongmei Sun ◽  
Brent Louie ◽  
Erik Evensen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Disease Activity ◽  
Signaling Pathways ◽  
Treatment Response ◽  
Immune Cell ◽  
Rheumatoid Arthritis Disease ◽  
Immune Cell Subsets ◽  
Systems Immunology ◽  
Stat Signaling

AbstractRheumatoid arthritis (RA), a chronic autoimmune disease characterized by circulating autoantibodies, involves many cytokine-mediated signaling pathways in multiple immune cell subsets. Most studies of immune cells in RA have limitations, such as analysis of a small number of cell subsets or pathways, and limited longitudinal data on patient phenotypes. In this study, we used an innovative systems immunology approach to simultaneously quantify up to 882 signaling nodes (Jak/STAT signaling readouts modulated by cytokines and other stimuli) in 21 immune cell subsets. We studied 194 RA patients and 41 controls, including 146 well-characterized RA patients prior to, and 6 months after, initiation of methotrexate or biologic agents from the Treatment Efficacy and Toxicity in RA Database and Repository (TETRAD). There was strikingly attenuated signaling capacity in RA patients in IFNα stimulation followed by measurement of phosphorylated STAT1 [IFNα→p-STAT1] in six immune cell subsets. Multiple nodes showed negative association with disease activity, including IFNα→STAT5 signaling in naive and memory B cells. In contrast, IL-6-induced STAT1 and STAT3 activation in central memory CD4-negative T cells showed a positive association with disease activity. Multiple nodes were associated with treatment response, including IFNα→STAT1 in monocytes and IL-6→STAT3 in CD4+ naive T cells. Decision tree analysis identified a model combining these two nodes as a high-performing classifier of treatment response to TNF inhibitors. Our study provides novel information on RA disease mechanisms and serves as a framework for the discovery and validation of biomarkers of treatment response in RA.

scholarly journals Developing new therapeutic approaches for rheumatoid arthritis: the continuing challenges of clinical assessments

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2019 ◽  
Author(s):  
David L. Scott
Keyword(s):  
Rheumatoid Arthritis ◽  
Intensive Therapy ◽  
Treatment Intensity ◽  
Optimal Management ◽  
Therapeutic Approaches ◽  
Optimal Care ◽  
Clinical Assessments ◽  
New Therapeutic Approaches ◽  
Different Types ◽  
Key Driver

The management of rheumatoid arthritis has changed dramatically over the last three decades. Improvements in clinical assessment have been a key driver of these changes. However, in the last five years, three areas of unresolved uncertainty have dominated specialist thinking in the field. These challenges comprise identifying the optimal management target, determining how best to reach this target by using intensive treatments, and individualising management because not all patients need or respond to identical treatments. The key problem that links each of these areas is balancing different types of evidence and is most readily appreciated in relation to treatment intensity. Giving more intensive therapy improves outcomes but also increases risks and, with biologic treatments, substantially increases drug costs. Specialists and healthcare funders need to agree on how best to rationalise optimal care for patients with what is most effective and safe and what is affordable.

scholarly journals Immunomodulation as a Therapy for Aspergillus Infection: Current Status and Future Perspectives

2018 ◽  
Vol 4 (4) ◽  
pp. 137 ◽  
Author(s):  
Chris Lauruschkat ◽  
Hermann Einsele ◽  
Juergen Loeffler
Keyword(s):  
Immune Cell ◽  
Current Knowledge ◽  
Antifungal Drugs ◽  
Current Status ◽  
Remission Induction ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Life Threatening ◽  
Broad Variety ◽  
Immunological Recovery

Invasive aspergillosis (IA) is the most serious life-threatening infectious complication of intensive remission induction chemotherapy and allogeneic stem cell transplantation in patients with a variety of hematological malignancies. Aspergillus fumigatus is the most commonly isolated species from cases of IA. Despite the various improvements that have been made with preventative strategies and the development of antifungal drugs, there is an urgent need for new therapeutic approaches that focus on strategies to boost the host’s immune response, since immunological recovery is recognized as being the major determinant of the outcome of IA. Here, we aim to summarize current knowledge about a broad variety of immunotherapeutic approaches against IA, including therapies based on the transfer of distinct immune cell populations, and the administration of cytokines and antibodies.

scholarly journals OP0100 MOLECULAR PROFILING OF PERIPHERAL IMMUNE CELL SUBSETS IN PATIENTS WITH RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 65.2-65
Author(s):  
P. C. Taylor ◽  
J. Liu ◽  
L. Zhuo ◽  
Y. Tian ◽  
T. Snyder ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Immune Cell ◽  
Life Sciences ◽  
Cell Subset ◽  
Chromatin Accessibility ◽  
Janus Kinase ◽  
Immune Cell Subset ◽  
Pathway Activity ◽  
Immune Cell Subsets

Background:Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects 1% of the world’s population. Several key biological functions are dysregulated in RA, manifesting clinically as pain, fatigue, and synovitis, with articular destruction, organ-based comorbidities, and functional decline. Defining immune dysregulation in the peripheral blood of patients (pts) with RA will help inform future work to assess the extent to which immune homeostasis can be therapeutically achieved for these pts.Objectives:To identify baseline molecular characteristics of the peripheral immune system, at the level of individual immune cell subsets, in pts with RA recruited to clinical trials of the oral, selective Janus kinase 1 (JAK1) inhibitor, filgotinib.Methods:Peripheral blood mononuclear cells (PBMC) were collected from 324 pts with moderate to severely active RA, who had an inadequate response to methotrexate ([MTX], FINCH-1;NCT02889796; n=109) or who were MTX naïve (FINCH-3;NCT02886728; n=215). PBMC were also collected from 50 demographically matched healthy volunteers (HV). The Immune Profiler platform was used to sort PBMC into 24 immune cell subsets, then quantify their gene expression and chromatin accessibility using RNA-seq and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), respectively. Differentially expressed genes (DEGs) and differentially accessible regions (DARs) were identified among immune cell subsets from pts with RA versus HV. Gene set signature scores of Molecular Signatures Database hallmark pathways were calculated using single sample gene set enrichment analysis (ssGSEA) to examine differences in pathway activity between groups.Results:A total of 14,500 sequencing datasets were generated from the pt and HV immune cell subsets. Among these, over 26,000 DEGs and 220,000 DARs were identified in RA versus HV (false discovery rate <0.05) across the 24 immune cell subsets. DEGs were identified in all immune cell subsets tested and were most pronounced in natural killer (NK) subsets; most DARs were detected in myeloid and NK subsets. ssGSEA revealed differential pathway signaling in RA versus HV across multiple functions at the immune cell subset level. Myeloid subsets from pts with RA often showed elevated pathway activities versus HV whereas B, T and NK subsets showed a general decrease. In particular, monocyte populations from pts with RA versus HV had elevated pathway activities involved in inflammatory response and interleukin-6/Janus kinase/signal transducer and activator of transcription 3 signaling. The B, T and NK subsets showed a general decrease in tumor necrosis factor-α signaling; conversely, monocyte subsets showed an increase. Prior MTX exposure did not have a notable impact on the detected molecular profile.Conclusion:Differences in gene expression, hallmark pathway activity, and chromatin accessibility were identified in RA versus HV at the immune cell subset level. Significant contributions to differences in chromatin accessibility identified in the myeloid and NK cell populations suggest that there are more active regulatory sequences in these cell types that are associated with RA. Further investigations based on these findings may increase understanding of the immune regulatory paradigm in the context of RA.Acknowledgments:This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Luting Zhuo Employee of: Gilead Sciences Inc., Yuan Tian Employee of: Gilead Sciences Inc., Thomas Snyder Employee of: Verily Life Sciences, Charlie Kim Employee of: Verily Life Sciences, Pouya Kheradpour Employee of: Verily Life Sciences, Kat Drake Employee of: Verily Life Sciences, Sam Kim Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

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