Medico - Scientific Background

The concept of autoinflammatory/autoimmune disease continuum (AADC)

Chronic inflammation, a condition present in various diseases including those with an immune component, is an important cause of morbidity/mortality in the developed world. Recent advances in the pathophysiology of autoinflammatory/autoimmune diseases have led to a re-examination of their nosology. It now appears that autoinflammatory and autoimmune diseases do not represent two distinct categories of disorders. Rather, they form a disease continuum ranging from pure autoinflammatory disorders to pure autoimmune diseases, encompassing a large panel of inflammatory diseases with some autoimmune component, and vice versa. A wide range of disorders fall into this disease category. These are rare or common disorders, whose management requires an integrated approach in which clinicians from internal medicine or medical specialties and research teams collaborate closely in translational research programs.

​Aims

WP1: Implementing deep-phenotyping and immunomics​

​WP leaders:​ A. Six, P. Benech, M. Rosenzwajg​​

• Aim 1: Designing a standardized database for integration of clinical and biological data
  

  ​​​We are developing a database following international standards. A dedicated coordination Cohort management team (CMT) will perform on site cohort monitoring for compliance and clinical research file and queries collection. CMT will liaise with clinicians, database managers, and scientists.

• Aim 2: Deep PhenOmics
  

  To reach a comprehensive understanding of the immune system, a complete representation of the diversity and complexity of the immune system in disease involves several overlapping levels and requires the integration of this information. For this goal, we will acquire clinical as well as flow cytometry, genomic, transcriptomic, proteomic, and deep sequencing TCR repertoire data. Standards procedures for Tregs/ Teffs sorting and deep immunophenotyping​ by flow cytometry have already been set up.

• Aim 3: Literature mining to qualify and quantify the domain model
  

  The aim is to apply text mining technologies to take advantage of literature of the domain to improve our comprehension of inflammatory and autoimmune diseases. This domain knowledge base will allow a more efficient analysis of genomic/proteomic data and study their relation to drugs and treatments.

WP2: Cross-phenotyping in the inflammatory/autoimmune diseases continuum

​WP leaders:​ S. Amselem, P. Cacoub, A. Six​

• Aim 1: Establishment of disease & healthy donor cohorts
  

  Thirteen caracteristic inflammatory and autoimmune diseases (i.e. type 1 diabetes, systemic lupus erythematosus/antiphospholipid syndrome, myositis, vasculitis, rheumatoid arthritis, ankylosing spondylitis,​ uveitis, FMF/TRAPS/CAPS,  Crohn's Disease, ulcerative rectocolitis, arthritis, muscular dystrophy) have been selected for cross-phenotyping modelling. Hundred patients per disease will be recruited together with a group of 100 healthy controls. Based on clinical & biological data collected, we will implement modelling schemes in order to identify pathophysiological signatures and biomarkers.

• Aim 2: Defining the normal Immunome
  

  The aim is to initiate an “Immuno-physiome” model of the immune system and define the ranges of normality and variability that exist between individuals through genetics, from young adult to elderly people. The challenge is to qualify and quantify perturbations occurring at the molecular and cell level through age. This task will be important to guide the interpretation of signatures & biomarkers obtained in the studied disease states.

• Aim 3: Defining the immunome of the different diseases studied
  

  The chosen autoimmune/inflammatory pathologies will be analyzed based on samples and clinical/biological data produced by WP1. For example, this comparative analysis across diseases will characterize the immunome:

  • between auto-Ab related diseases and their negative counterpart,
  • between organ specific and non organ specific autoimmune diseases,
  • of kidney involvement in different autoimmune diseases,
  • ​of each IAD before and after treatment (i.e. active versus non active disease)
• Aim 4: Identification of novel genes involved in AISs
  

  ​This aim will allow to decipher the molecular basis of familial forms and syndromic cases of inflammatory/autoimmune diseases. The search for new genes involved in AISs will be conducted following complementary state-of-the-art approaches (SNPs and exome sequencing). These studies should contribute to the identification of molecular markers of diagnostic value. ​

• Aim 5: T repertoire analyses by deep sequencing
  

  Deep sequencing analysis will be carried out in order to characterize the extent of repertoire diversity perturbation associated with inflammatory or autoimmune disease processes. These analyses will provide new hypotheses on the type of immune responses involved, and will help to identify candidate antigens which will be targeted by ad hoc biotherapies.​

• Aim 6: Data modelling & Biomarker discovery
  

  This aim will elaborate and validate data modelling schemes needed to serve aims of WP2. This includes:

  • Elaboration of a static structural model presenting components involved in disease,
  • Extraction of molecular and cellular parameters being specific for sub-groups of the studied population,
  • Identification of disease- or pathological process-specific characteristic signatures & biomarkers,
  • Construction of dynamical models providing mechanistic descriptions of the disease process.

WP3: Biomarkers and biotherapies evaluation

​WP leaders:​ D. klatzmann, F. Berenbaum, V. Doppler​

• Aim 1: Clinical investigation of Biotherapies
  

  In T1D, we have an ongoing series of trials that are planned, which will give us important information relative to dose and scheme of administration, aspects that are important and not yet fully investigated. Based on this knowledge, we will design the trials to be performed in our diseases of interest for this program. In uveitis, for which we have a planed clinical trial investigating the intra-occular injection of ex vivo activated Treg, we will test the adjunction of IL-2 in situ or parenterally, with the aim to improve the efficacy of the injected cells. This will be compared to injection of IL-2 alone. Similarly, in IBM for which we have a planed clinical trial investigating the injection of ex vivo expanded Treg injected parenterally, we will test the adjunction of IL-2. This will be compared to injection of IL-2 alone. Finally, RA is our next target for testing IL-2 in a highly inflammatory disease.

• Aim 2: Development of new biotherapies
  

  The aim is to validate the identified potential bio-therapeutic tools or targets delivered by WP1, WP2 and to develop new human biotherapies. This includes:

  • ​Development of drug or biological based therapies
  • Development of antigen-based therapies
  • ​Optimization of Treg-cell based therapies​