The Milieu Intérieur project has a potential strong impact on public health, as the data generated will provide a foundation for defining perturbations in an individual’s immune responses, thus laying the foundation for personalized medicine. Several teams within the Consortium have proposed comparison studies in disease states thus setting the foundations for phase 4 of the project (association studies in disease settings). In addition, it is planned to extend the Milieu Intérieur approach to other healthy cohorts in the world and to define the impact on the immune system of diverse ethnic background and environment; a pilot study is already initiated.
Genes, signaling pathways and regulatory circuits involved in the pathogenesis of spondyloarthritis (SpA)
Lars Rogge’s team (Institut Pasteur) has set a pilot study with Pr Maxime Dougados at Hôpital Cochin in spondyloarthritis patients (SpA) with the main goal of defining genes, signaling pathways and regulatory circuits involved in the pathogenesis of spondyloarthritis (SpA). In particular, the objective is to address the complexity of genetic interactions and define specific combinations of single nucleotide polymorphisms that affect immune cell functions and pathology. The TruCulture® kits developed for the LabEx clinical study were used for the pilot study whose target is to recruit 12 patients.
This project builds on concepts and expertise developed in the context of a collaborative study of the Rogge and Dougados teams that has linked genetic variation at loci associated with the IL-23 signaling pathway and the function of Th1 and Th17 subsets in SpA.
Multiparametric evaluation of the immune status of multiple sclerosis patients
Fréderique Michel’s team (Institut Pasteur) has initiated a pilot study of patients with Multiple Sclerosis with Drs C. Papeix and E. Maillard at Hôpital Pitié-Salpêtrière. The relapsing-remitting form of this chronic inflammatory demyelinating autoimmune disease of the central nervous system is commonly treated with interferon beta (IFNb). However, around 30% of treated patients do not or poorly respond to the treatment.
The objective is to explore in vivo and ex vivo the immune status of 30 RR-MS patients treated or not with IFNb, using a multiparametric approach including multicolor flow cytometry and large scale profiling of cytokine and gene expression. The final goal is to determine correlative links with the clinical status of patients and to identify predictive cellular, cytokine and gene-based biomarkers of IFNb responsiveness. The current project is conducted in close collaboration with the LabEx Milieu Intérieur (MI), using the whole blood TruCulture system and state-of-the-art technologies, and integrating the data with those obtained with the MI 1000 healthy donors.
Stratifying tuberculosis disease using whole blood stimulation
Matthew Albert and Darragh Duffy (Institut Pasteur) are engaged in a pilot study in collaboration with Dr. Thomas Scriba (South African Tuberculosis Vaccine Initiative) to stratify patients with active and latent tuberculosis. This research project is funded by the Bill & Melinda Gates Foundation. The objective of this project is to establish feasibility for a new generation of in vitro diagnostic (IVDs) tools, applied to proof-of-concept studies in Mycobacterium tuberculosis (MTB) infected persons and patients with TB disease. Implementation of our immune monitoring solutions will ensure a positive impact on patient management and clinical research projects: optimizing patient stratification, treatment, and supporting new drug/vaccine trials. Overall, this technical approach will establish a stable, long-term mechanism to support the use of functional immune diagnostic tests for a multitude of disease states.
Type 1 Diabetes and innate immunity
This is a collaboration between Kristin Tarbell (NIH, USA) and Darragh Duffy (Institut Pasteur). They will assess innate reactivity in Type 1 Diabetes (T1D) patients and age-matched controls. Information on autoimmune-mediated changes in innate responses may help them understand pathogenesis, and importantly, to decipher the innate signals that may need to be blocked when giving antigen for tolerance induction in future studies to prevent or treat T1D. The hypothesis to be tested in this study is that response to in vitro innate immune stimulation will differ in blood samples from T1D patients compared to healthy controls. This is a natural history study, in which innate immunity will be evaluated in T1D patients and healthy controls. Patients are currently being recruited at the Benaroya Institute, Seattle, USA (20 new-onset T1D patients and 20 healthy controls, age 10-30 years old). Fasting blood samples will be taken, and stimulated in vitro with innate ligands.
Juvenile Idioparthic Arthritis
Richard Lee (NHS Bristol, UK) and Darragh Duffy (Institut Pasteur) have launched a pilot study with the objective to test the ability of TruCulture whole blood stimulation to monitor immune response changes during anti-IL6R Ab treatment (Tocilizumab) that is performed in the Aptitude clinical study. The hope is that this approach could be used to predict or monitor treatment efficacy.
Healthy Human Global Project (HHGP)
The consortium has recently initiated the Healthy Human Global Project (HHGP) whose objective is directly inspired from Milieu Intérieur approach: in order to expand the geographical reach and ethnic diversity of the project, the Healthy Human Global Project (HHGP) will initiate studies in healthy cohorts within the Pasteur International Network. This will establish a global resource for understanding how different genetic backgrounds and local environmental factors contribute to heterogeneity in human immune responses.
The HHGP-Senegal project will initiate a pilot study in an African setting. To do this, the consortium Milieu Intérieur is working with the Institut Pasteur in Senegal to recruit 48 healthy donors in two villages with different genetic background and ecosystems. One important objective of HHGP-Senegal is to evaluate the feasibility and requirements of a larger scale study in this country, to provide technical and logistical support for its implementation, and to establish preliminary data.