Adaptive human immunity drives remyelination in a mouse model of demyelination.
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 favourable 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 or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Mohamed
M
El Behi
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Charles
C
Sanson
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Corinne
C
Bachelin
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Léna
L
Guillot-Noël
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Jennifer
J
Fransson
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.|Assistance Publique-Hôpitaux de Paris, Neurology Service, Hôpital Saint Antoine-HUEP, Paris 12, France.
Bruno
B
Stankoff
Assistance Publique-Hôpitaux de Paris, Neurology Department Pitié Salpétrière University Hospital Paris, France.
Elisabeth
E
Maillart
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Nadège
N
Sarrazin
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Vincent
V
Guillemot
School of Brain and Behavioral Sciences, The University of Texas, Dallas, USA.
Hervé
H
Abdi
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Isabelle
I
Cournu-Rebeix
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.|Assistance Publique-Hôpitaux de Paris, Neurology Service, Hôpital Saint Antoine-HUEP, Paris 12, France.|Assistance Publique-Hôpitaux de Paris, Neurology Department Pitié Salpétrière University Hospital Paris, France.
Bertrand
B
Fontaine
Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013 Paris, France.
Violetta
V
Zujovic
D056704:Adaptive Immunity / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017690:Cell Transplantation; D054415:Chemokine CCL19 / Q000276:immunology; D003711:Demyelinating Diseases / Q000276:immunology*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D009186:Myelin Sheath / Q000276:immunology*; D058953:Neural Stem Cells / Q000276:immunology; D009836:Oligodendroglia / Q000276:immunology / Q000473:pathology; D055815:Young Adult
C515460:CCL19 protein, human; D054415:Chemokine CCL19; D008244:Lysophosphatidylcholines
lymphocytes; multiple sclerosis; neuroinflammation; remyelination