Adaptive immunity drives remyelination failure or success in multiple sclerosis
ECTRIMS Online Library. Zujovic V. 10/26/17; 202495; 140
Violetta Zujovic
Violetta Zujovic
Contributions
Abstract

Abstract: 140

Type: Oral

Abstract Category: Pathology and pathogenesis of MS - 20 Repairing mechanisms

One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favorable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells.
Therefore, we developed a new paradigm by grafting healthy donor (HD) or multiple sclerosis patient lymphocytes (LT) in the demyelinated lesion of Nude mice spinal cord.
We show that LT play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis LT compared to those grafted with HD LT. Mechanistically, we demonstrated in vitro that LT-derived mediators influenced oligodendrocyte precursor cells (OPC) differentiation through a crosstalk with microglial cells. Among mice grafted with LT from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing LT secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in OPC differentiation and validated CCL19 as a target to improve remyelination: specifically, exogenous CCL19 abolished OPC differentiation observed in patients with high remyelination pattern.
Multiple sclerosis LT exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies. In parallel, we discovered that the genetic profile of patients can predict their remyelination efficacy, we are therefore working on discovering biomarkers to be able to predict disease evolution in patients.
Disclosure: C. Sanson : nothing to disclose
M. El Behi : nothing to disclose
C. Bachelin : nothing to disclose
L. Guillot-Noël : nothing to disclose
J. Fransson : nothing to disclose
B. Stankoff : nothing to disclose
E. Maillart : nothing to disclose
N. Sarrazin : nothing to disclose
V. Guillemot : nothing to disclose
H. Abdi : nothing to disclose
I. Cournu-Rebeix : nothing to disclose
B. Fontaine : nothing to disclose
V. Zujovic : nothing to disclose

Abstract: 140

Type: Oral

Abstract Category: Pathology and pathogenesis of MS - 20 Repairing mechanisms

One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favorable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells.
Therefore, we developed a new paradigm by grafting healthy donor (HD) or multiple sclerosis patient lymphocytes (LT) in the demyelinated lesion of Nude mice spinal cord.
We show that LT play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis LT compared to those grafted with HD LT. Mechanistically, we demonstrated in vitro that LT-derived mediators influenced oligodendrocyte precursor cells (OPC) differentiation through a crosstalk with microglial cells. Among mice grafted with LT from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing LT secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in OPC differentiation and validated CCL19 as a target to improve remyelination: specifically, exogenous CCL19 abolished OPC differentiation observed in patients with high remyelination pattern.
Multiple sclerosis LT exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies. In parallel, we discovered that the genetic profile of patients can predict their remyelination efficacy, we are therefore working on discovering biomarkers to be able to predict disease evolution in patients.
Disclosure: C. Sanson : nothing to disclose
M. El Behi : nothing to disclose
C. Bachelin : nothing to disclose
L. Guillot-Noël : nothing to disclose
J. Fransson : nothing to disclose
B. Stankoff : nothing to disclose
E. Maillart : nothing to disclose
N. Sarrazin : nothing to disclose
V. Guillemot : nothing to disclose
H. Abdi : nothing to disclose
I. Cournu-Rebeix : nothing to disclose
B. Fontaine : nothing to disclose
V. Zujovic : nothing to disclose

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