Rheumatoid arthritis (RA) is a common disease which results in chronic inflammation of joint tissues, joint destruction and vascular damages.
RA is an auto-immune disease characterized by the production of auto-antibodies, including anti-CCP or ACPA. Genetic susceptibility and environnemental factors like smoking are known to favour its appearance. RA affects 0,3% of the population in France and about 50 million people in the world.
The treatment of RA combinate local ans systemic treatments. Methotrexate is the most commonly used drug. Over the past few years, new therapeutic targets have been discovered, leading to the development of new drugs specifically targeting a cytokine or a cell type. These targeted treatments are called « biotherapies » and are mainly monoclonal antibodies or receptors of cytokines.
The most used of these drugs are the anti-TNFalpha and biotherapies targeting the Il-6 receptor, the interaction between lymphocyte and dendritic cell, B cells or Il-1.
Due to its frequency, RA is a good model for the study of targeted treatments. Other inflammatory rheumatic diseases as well as other inflammatory diseases such as Crohn’s disease and psoriasis are also fields of application for strategies of biotherapies.
The identification of molecular and cellular players for a therapeutic use is a fundamental part of our research unit. Our team thus develops new therapeutic strategies and research of mechanisms of action of targeted therapies or biotherapy.
Cellular immunoregulation and cytokines in rheumatoid arthritis
T cells are necessary for the initiation and development of RA.
They are activated by antigen-presenting cells, including dendritic cells. Current data on lymphocyte differentiation show that regulatory T cells that express the transcription factor FoxP3, a subpopulation of T cells, negatively regulate immune responses and could be key players to control the disease.
We study these regulatory cells and their role in relation to other lymphocyte populations in RA and in experimental models such as collagen-induced arthritis and arthritis in mice transgenic for the human TNFalpha. We also study the relationship between these cells and biotherapy of RA.
We ask in particular whether they are involved in resistance to targeted treatemnt such as anti-TNF agents.
Among the cytokines involved in the pathogenesis of RA, IL-33 could play a special role because it is both an alarmine and a cytokine inducing an immune type 2 response. We study its role in an experimental model of RA by elucidating its involvement in the initiation of the disease, but also by studying the consequences of its administration on modulatory cells (Tregs, ILC2 ...).
Neutrophils and innate immunity in rheumatoid arthritis
Polymorphonulear neutrophils are important for the development of inflammatory responses,
as they are the first cells recruited at sites of inflammation. Activated neutrophils are particularly abundant in the joints of patients with RA. However, some neutrophil functions as well as mechanisms leading to neutrophil activation remain unknown. Moreover, new functions have been attributed to neutrophils, like the ability to act as antigen-presenting cells activating T cells. Similarly, neutrophils interact with dendritic cells, suggesting a link between innate and adaptive immunity as well as another way of immunoregulation, making neutrophils a promising therapeutic target.
For all those reasons, we are studying the mechanisms of neutrophil activation in RA and collagen-induced arthritis in mice and the consequences on the development of immune and inflammatory responses. We are analyzing in particular the role of Toll-like receptor (TLR) and endogenous ligands, the complement system and the cross-talk with other cells, like the proinflammatory Th17 cells. We are also studying netosis and some soluble mediators produced by neutrophils. The goal is to identify pathogenic mechanisms and new targets for future therapeutic approaches.
Collaborations for this theme: Prof. Marina Botto (London, England), Prof. Bernhard Singer (Essen, Germany), Prof. Guy Serre (Toulouse, France).
Rheumatoid arthritis and vascular inflammation
In RA, microvascular and macrovascular dysfunctions might result in microvascular and macrovascular diseases.
Among microvascular dysfunctions, tissular angiogenesis is well known and among macrovascular dysfunctions, atheromatous diseases increases mortality risk in RA. Apart from the usual risk factors (hypercholesteronemia, hypertension, smoking, obesity), other risks could be expected in cardiovascular events including long term systemic inflammation, molecules produced by cells in the inflamed joints or treatments used such as corticoid, anti-inflammatory products or more recent biotherapies.
We assume that both joints and systemic inflammations might play an active role in extra articular events. Using experimental arthritis models, we study the endothelial dysfunctions which might be responsible for vascular dysfunctions in large vessels (aorta), in this inflammatory context. Our goal is to understand the link between arthritis development and vascular lesions formation to identify new targets for future therapeutic approaches.
Biotherapies of inflammation
This line of research concerns the design of new tools blocking the inflammation,
the study of their action (experimental models) and their mode of action (in humans or in experimental models).
Several categories of biotherapies are :
Mode of action of biotherapies used in humans: anti-TNFalpha are the most used for RA. Their direct anti-inflammatory effect (the blocking of synovial TNFalpha can locally reduce inflammatory agents) guided their development. It appears now that the action of TNFalpha on immune system cells may explain the action of anti-TNFalpha on cell populations that regulate the immune response. We study the role of regulatory T cells, Th17 cells, Th1 and Th2 in the effectiveness of anti-TNFalpha or other biotherapies.
Anti-cytokine vaccination: the study of molecular players involved in the inflammatory phenomena led us to develop strategies of specific inhibition. Classic anti-cytokine biotherapies are passive immunotherapies. We have developed strategies for active immunotherapy (or vaccination). Collaboration with the company Neovacs (Paris) allowed us to demonstrate the benefits of a vaccination against TNF in an arthritis model. This vaccine is a heterocomplex of the entire cytokine and KLH; a phase 1 clinical trial was carried out in Crohn's disease and a phase 2 trial in RA; an international phase 2B trial is in progress in RA. This work continue to clarify the mechanism of action of this vaccine, called TNF-Kinoid.
The involvement of certain cells of innate immunity at an early stage is also studied. Other cytokines are also analyzed. We also study the possibility of generating antibodies to cytokines using a simplified strategy, with peptides of cytokines, with the collaboration of Peptinov Inc.. Work is in progress for the study of vaccination against IL-1 in RA, thanks to funds received from public organization grouped in “FUI” funds (Conseil Général de la Seine Saint-Denis, le Conseil Régional d’Ile de France, la Banque Publique d’Investissement-Oseo, le Ministère de la recherche). We are going on working with vaccines targeting VEGF, IL-23, IL-6 (as examples).
Within the rheumatology department of the Avicenne Hospital, clinical research is growing, in close contact with the laboratory.
- Nycthemeral variability in the detection of arthritis by ultrasound in RA.
- Clinical trial (phase 2): active immunotherapy against TNF using TNF Kinoid (multicenter, international); promoter: Neovacs (Paris)
- Clinical trials and registries of registered biotherapies
- Metabolomic studies in rheumatoid arthritis (collaboration Inserm U967/CEA)
- Bone involvement in inflammatory diseases
- Omega-3 fatty acids an rheumatoid arthritis
- Impact of food intake and environmental factors in rheumatoid arthritis and spondyloarthropathies (collaboration with UREN, Inserm U557/CEA/CNAM); nutrinet study: https://www.etude-nutrinet-sante.fr
Rôle de l'environnement
Les facteurs génétiques n’expliquent qu’une partie de la maladie. C’est ainsi que l’environnement joue un rôle déterminant dans l’apparition de la maladie. Le facteur le mieux mis en évidence en est le tabac. Le fait de fumer est un facteur de risque certain de la polyarthrite rhumatoïde, de sa gravité, de son évolution vers plus de destruction articulaire, de sa résistance relative aux traitements.
Nous étudions le rôle de la pollution, et avons entrepris une étude sur le rôle de l’exposition à la silice dans la survenue d’une polyarthrite rhumatoïde (collaboration avec Sciences Po Paris). Nous étudions également le rôle des facteurs alimentaires, notamment certains lipides, dans la maladie ; pour ces travaux, nous collaborons avec l’équipe de Serge Hercberg à Bobigny (voir l’onglet « Etudes cliniques ») et utilisons les données de la cohorte nationale ESPOIR.