LYMPHOCYTES: SUPERVISORS OF MICROGLIAL ACTIVATION AND REMYELINATION in MUTIPLE SCLEROSIS PATIENT. – SMARTinMS

In multiple sclerosis (MS), the extent and efficacy of remyelination is highly variable among patients and this variability determines patient disability accrual. The burden of innate immune cells activation, measured by positron emission positron emission tomography (PET), was also recently showed to strongly influence individual trajectories of disability worsening. Inflammation is responsible for myelin destruction and axonal degeneration leading to the most severe symptoms in MS, but it is also essential for remyelination to occur. It is therefore crucial to decipher precisely the proper inflammatory context leading to a successful repair or to a chronic lesion.
Our principal objective is to define precisely the proper inflammatory context leading to successful myelin repair in MS patient.
In this project we will evaluate patients with either a relapsing-remitting or a progressive form of MS (secondary progressive or primary progressive), and determine their individual remyelination profiles using 18F-Florbetaben PET-MR (magnetic resonance), together with the extent of innate immune cells activation using 18F-DPA-714 PET. We will include 20 patients for each phase, (total 40 patients) and a group of healthy controls (10 HC matched for age and gender to the group with relapsing MS, 10 HC matched for age and gender to the group with progressive MS), to enable the generation of the adequate thresholds for each brain voxel as “remyelinatng” or “inflammatory- active” on 18F-Florbetaben PET of 18F-DPA-714 PET respectively. The relationship between individual remyelination capacities and neuro-inflammation will be investigated in vivo for the first time. In parallel, a high dimensional profiling of their lymphocytes (LY) will enable to define the LY subset associated with remyelination failure or success. Next we will decipher experimentally how patients LY determine the remyelination success or failure, and trigger chronic activation of lesions, in an in vivo humanized animal model of MS lesion, elucidating more precisely the molecular and cellular actors in an in vitro culture system following both microglial activation and OPC differentiation steps. A powerful bio-informatic integrative analysis strategy will identify the LY population that inhibit repair. Novel biomarkers potentially predicting bad remyelination capacities and disability worsening will be generated, and novel remyelination strategies will be opened.
On this basis, the SMART in MS project has been organized as a translational discovery platform based on 4 major research pillars serving 4 major specific aims (SA). First (SA1), defining the individual inflammatory and remyelination profiles of MS patients during the relapsing and the progressive phase of the disease. Second (SA2), elaborating a high-dimensional profiling of MS patient LY associated with remyelination failure or success. Third (SA3) testing in vivo and in vitro the effect of patients LY (whole population or LY subsets) on the remyelination process. Last (SA4), applying an elaborated multivariated analysis to decipher the cellular and molecular player for efficient remyelination.
SMART in MS will therefore capitalize on a unique research continuum between clinicians neuroimaging specialists, statisticians, immunologists and neurobiologists. By combining their expertise in a translational research process, the project will aim at identifying and pharmacologically validating specific immune pathways that could be targeted to both stop the immune aggression and maintain the appropriate level of immune stimulus to promote endogenous remyelination. One step further, the generated insights and results will give fuel to research and development agreements with third parties to develop a new-generation of therapeutic compounds allowing for a better long-term management of MS and other immune mediated demyelinating diseases.