Since the initiation of the Milieu Intérieur project in 2011, our initial objectives — in terms of major scientific questions, biobanking, data production, teaching & training, and structuring a new community of trans-disciplinary researchers — have been
successfully achieved. Some of these achievements are highlighted below and consult all the MI publications here
Establishment of a human cohort
1,000 healthy volunteers - 1:1 sex ratio; stratified across 5 decades of life from 20 to 69 years of age - were recruited. For each individual, we obtained
(i) a 44-page questionnaire (eCRF) of lifestyle and demographic variables to delineate the factors characterising a healthy immune response,
(ii) whole blood for immune phenotyping, immune stimulation and genomic analysis, and (iii) faecal samples and nasal swabs for metagenomic studies of microbiota. Punch skin biopsies were also taken to generate primary fibroblast lines and induced Pluripotent Stem cells (from selected donors) to enable mechanistic studies.
Consult the publication for more information
Definition of protein and transcriptional immune signatures
To define the boundaries of a healthy immune response, we developed whole-blood
stimulation systems utilizing TruCulture technology. In partnership with Myriad RBM, we validated a total of 40 conditions, including bacteria, fungi, and live viruses. We have defined the protein and transcriptional signatures generated by each of the stimulation conditions, increasing our understanding of the inter-individual variation in immune responses to complex stimuli.
More information on the protein signatures
More information on the transcriptional signatures
Genetic characterisation of the human cohort
The 1,000 subjects have been genetically characterised using two whole-genome genotyping arrays (HumanOmniExpress-24 and HumanExome-12 BeadChip, Illumina, California). These genetic variants have allowed characterisation of the genomic variability of our cohort to conduct association studies (e.g. genetic variants controlling transcriptional responses to infection, eQTLs). The complete genome sequences, at 30x coverage, of the entire cohort are now being generated in collaboration with the CNRGH-CEA (Evry, France).
Genetic, intrinsic and environmental determinants of immune response variation
Four major population-based studies have been performed thus far:
The first aimed at understanding the determinants of variation of immune cells in whole blood. Through the combination of genetic data, >100 lifestyle/physiological variables, and 166 immune cell parameters in the 1,000 individuals, we identified 15 loci associated with immune cell variation and found that smoking, age, sex and latent infection with cytomegalovirus are the main non-genetic factors affecting immune cell variation. Read the publication
The same concept was applied to transcriptional responses to bacterial, viral and fungal infections. We found that age and sex affected the transcriptional response of most immune-related genes, while genetic factors had a stronger effect on immune gene regulation than age and sex, yet affected a smaller number of genes. Read the publication
The third analysis has identified the respective contributions of age, sex, and genetics to humoral response to vaccination and latent viral infection. Read the publication
The fourth study investigated the determinants of thymic function, providing unique insights into the role of a common genetic variant within the T cell receptor gene locus. Read the publication
Building a sample repository and data warehouse.
Given that a large number of biological samples and data sets have been generated,
careful storage, archiving, data integration and data sharing have all been key objectives of our project. We have utilised the Open Source platform LabKey (www.labkey.org) as it provides a full-featured data warehouse to store, curate, and query the data in a secure and traceable manner. All data generated, alongside the eCRF variables, have been integrated into the warehouse and data sharing and visualization tools have been created to allow the community to use and mine generated data sets. This has included the generation of 5 Shiny web-based applications, and the use of the Synapse ecosystem (maintained by our partner Sage Bionetworks).
Applying the MI concept to disease settings
We have also succeeded in translating the knowledge acquired in healthy donors to different disease conditions, using the 1,000 healthy donors as a reference control. 18 clinical studies that are funded independently of the LabEx are ongoing or planned. These are initiated by MI partners or external collaborators. The diseases studied range from infection (e.g. tuberculosis, viral hepatitis, and urinary tract infection) to autoimmunity (e.g. spondyloarthritis, multiple sclerosis, and type I diabetes) and allergy, highlighting the broad applicability of our work.
Read more about the Clinical Studies
Teaching and training
MI is strongly committed to increasing the training opportunities for translational research, immunology and genetics.
Read more about MI Teaching and Training
Impact of MI on the ecosystem
MI has fostered a consortium of 45 laboratories, including a young research group (G5) headed by Hugo Mouquet (who went on to create a startup Spikimm), uniting multi-disciplinary expertise. Our research program has emerged as a national and international reference for immune phenotyping; e.g., MI is providing tools or being used as a reference for the Afribiota Project (IP, funded by Total), the European FOCIS (Federation of Clinical Immunology Societies) Centers of Excellence project, the PersImmune immunodeficiency cohort (Copenhagen, Denmark), the Viral Resistance Project (TCD, Ireland), and the Human Vaccine Project. MI has also attracted international scholars that have come as visiting Professors, including Magnus Fontes (Lund University), Philip De Jager (Harvard University), Laurent Excoffier (University of Bern), and Guy Sella (Columbia University). Finally, highlighting the quality of the different partners of the MI consortium, it is worth mentioning that 10 MI laboratory heads have obtained external funding from the European Research Council (ERC).
The MI consortium has established a number of industrial partnerships, including (i)
Myriad RBM (USA) and HOT Screen (Germany) for the commercialization of 27 new
whole blood TruCulture stimulation devices, (ii) Miltenyi Biotec (Germany) for the standardization of flow cytometry phenotyping protocols, (iii) a joint program with the Nutrinet-study (nutrition and microbiota), and (iv) a long-standing partnership with Institut Roche on cancer immunotherapy. So far, 2 filed patents and 2 invention disclosures have been generated. We have also established a large number of clinical collaborations, highlighting the public health impact of MI. Given our desire to communicate the results of MI to the public, we created a MI video released on YouTube, have an active social media presence (Twitter, LinkedIn, ResearchGate), and MI scientists organized education classes to raise school children’s awareness towards microbes, hygiene, research, and vaccination.