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Adaptive human immunity drives remyelination in a mouse model of demyelination

View Article: PubMed Central - PubMed

ABSTRACT

The factors that determine whether remyelination fails or succeeds in multiple sclerosis remain unknown. By grafting lymphocytes from patients into demyelinated lesions in mice, El Behi, Sanson et al. show that lymphocytes differ in their ability to induce remyelination. Unravelling the basis of this heterogeneity reveals prerequisites for efficient myelin repair.

No MeSH data available.


Related in: MedlinePlus

Multiple sclerosis patient lymphocytes impede oligodendrocyte remyelination. Schematic of human lymphocyte influence on remyelination assay (A). Forty-eight hours after chemically-induced demyelination in the dorsal spinal cord of nude mice, healthy donor (HD, B and D) or multiple sclerosis patient (MS, C and E) lymphocytes were grafted at the lesion site or no cells were added (NG). After 21 days, oligodendrocyte differentiation was assessed using the combination Olig2/CC1 to distinguish between mature oligodendrocytes (white arrow heads: Olig2+CC1+ cells, B–E) and immature cells (white arrows: Olig2+CC1- cells, B–E). The number of Olig2+ cells and the percentage Olig2+CC1+ cells over Olig2+ cells (F) were evaluated in three independent experiments with three non-grafted mice (NG) per experiment, healthy donors (n = 8 individuals) and multiple sclerosis patients (n = 9, 3–5 grafted mice per individual). **P < 0.01, unpaired, two-tailed Student’s t-test. A second set of mice was processed for electron microscopy. Beside the mice grafted with the lymphocytes of the healthy donor subgroup (G and J), two subgroups of multiple sclerosis patients were considered (N): multiple sclerosis patients with a low (pink triangle) % of Olig-2+CC1+ (H and K, Patients 7–9) and patients with a High (purple triangle) % of Olig-2+CC1+ (I and L, Patients 1–5). Toluidine blue stained semi-thin section of lesion reveals the lesion area, delineated by a pink line (G–I). Ultrastructure analysis (J–L) was used to highlight axons remyelinated by oligodendrocytes (green), by Schwann cells (blue) or non-remyelinated (yellow) in lesions grafted with lymphocytes from the multiple sclerosis Low subgroup (n = 3, K) compared to those grafted with lymphocytes from healthy donors (n = 6, J) or the multiple sclerosis High subgroup (n = 5, L). Three to five mice were grafted for each individual. Remyelination was evaluated by measuring the total area of remyelination conducted by oligodendrocytes (M). *P < 0.05, **P < 0.01. One-way ANOVA and Tukey’s multiple comparison test. Scale bars = 100 µm in G–I; 50 µm in B–E and 5 µm in J–L.
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awx008-F1: Multiple sclerosis patient lymphocytes impede oligodendrocyte remyelination. Schematic of human lymphocyte influence on remyelination assay (A). Forty-eight hours after chemically-induced demyelination in the dorsal spinal cord of nude mice, healthy donor (HD, B and D) or multiple sclerosis patient (MS, C and E) lymphocytes were grafted at the lesion site or no cells were added (NG). After 21 days, oligodendrocyte differentiation was assessed using the combination Olig2/CC1 to distinguish between mature oligodendrocytes (white arrow heads: Olig2+CC1+ cells, B–E) and immature cells (white arrows: Olig2+CC1- cells, B–E). The number of Olig2+ cells and the percentage Olig2+CC1+ cells over Olig2+ cells (F) were evaluated in three independent experiments with three non-grafted mice (NG) per experiment, healthy donors (n = 8 individuals) and multiple sclerosis patients (n = 9, 3–5 grafted mice per individual). **P < 0.01, unpaired, two-tailed Student’s t-test. A second set of mice was processed for electron microscopy. Beside the mice grafted with the lymphocytes of the healthy donor subgroup (G and J), two subgroups of multiple sclerosis patients were considered (N): multiple sclerosis patients with a low (pink triangle) % of Olig-2+CC1+ (H and K, Patients 7–9) and patients with a High (purple triangle) % of Olig-2+CC1+ (I and L, Patients 1–5). Toluidine blue stained semi-thin section of lesion reveals the lesion area, delineated by a pink line (G–I). Ultrastructure analysis (J–L) was used to highlight axons remyelinated by oligodendrocytes (green), by Schwann cells (blue) or non-remyelinated (yellow) in lesions grafted with lymphocytes from the multiple sclerosis Low subgroup (n = 3, K) compared to those grafted with lymphocytes from healthy donors (n = 6, J) or the multiple sclerosis High subgroup (n = 5, L). Three to five mice were grafted for each individual. Remyelination was evaluated by measuring the total area of remyelination conducted by oligodendrocytes (M). *P < 0.05, **P < 0.01. One-way ANOVA and Tukey’s multiple comparison test. Scale bars = 100 µm in G–I; 50 µm in B–E and 5 µm in J–L.

Mentions: In nude mice, spontaneous remyelination occurs after focal demyelination from lysophosphatidylcholine (LPC) injection and is completed within 4 weeks (Jeffery and Blakemore, 1995). To evaluate how lymphocytes influence remyelination, we combined LPC-induced demyelination in the spinal cord of nude mice and the graft within the lesion 48 h after demyelination of 105 activated lymphocytes isolated from blood samples of healthy control subjects and patients with multiple sclerosis (Table 1, Supplementary Table 2 and Fig. 1A).Table 1


Adaptive human immunity drives remyelination in a mouse model of demyelination
Multiple sclerosis patient lymphocytes impede oligodendrocyte remyelination. Schematic of human lymphocyte influence on remyelination assay (A). Forty-eight hours after chemically-induced demyelination in the dorsal spinal cord of nude mice, healthy donor (HD, B and D) or multiple sclerosis patient (MS, C and E) lymphocytes were grafted at the lesion site or no cells were added (NG). After 21 days, oligodendrocyte differentiation was assessed using the combination Olig2/CC1 to distinguish between mature oligodendrocytes (white arrow heads: Olig2+CC1+ cells, B–E) and immature cells (white arrows: Olig2+CC1- cells, B–E). The number of Olig2+ cells and the percentage Olig2+CC1+ cells over Olig2+ cells (F) were evaluated in three independent experiments with three non-grafted mice (NG) per experiment, healthy donors (n = 8 individuals) and multiple sclerosis patients (n = 9, 3–5 grafted mice per individual). **P < 0.01, unpaired, two-tailed Student’s t-test. A second set of mice was processed for electron microscopy. Beside the mice grafted with the lymphocytes of the healthy donor subgroup (G and J), two subgroups of multiple sclerosis patients were considered (N): multiple sclerosis patients with a low (pink triangle) % of Olig-2+CC1+ (H and K, Patients 7–9) and patients with a High (purple triangle) % of Olig-2+CC1+ (I and L, Patients 1–5). Toluidine blue stained semi-thin section of lesion reveals the lesion area, delineated by a pink line (G–I). Ultrastructure analysis (J–L) was used to highlight axons remyelinated by oligodendrocytes (green), by Schwann cells (blue) or non-remyelinated (yellow) in lesions grafted with lymphocytes from the multiple sclerosis Low subgroup (n = 3, K) compared to those grafted with lymphocytes from healthy donors (n = 6, J) or the multiple sclerosis High subgroup (n = 5, L). Three to five mice were grafted for each individual. Remyelination was evaluated by measuring the total area of remyelination conducted by oligodendrocytes (M). *P < 0.05, **P < 0.01. One-way ANOVA and Tukey’s multiple comparison test. Scale bars = 100 µm in G–I; 50 µm in B–E and 5 µm in J–L.
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awx008-F1: Multiple sclerosis patient lymphocytes impede oligodendrocyte remyelination. Schematic of human lymphocyte influence on remyelination assay (A). Forty-eight hours after chemically-induced demyelination in the dorsal spinal cord of nude mice, healthy donor (HD, B and D) or multiple sclerosis patient (MS, C and E) lymphocytes were grafted at the lesion site or no cells were added (NG). After 21 days, oligodendrocyte differentiation was assessed using the combination Olig2/CC1 to distinguish between mature oligodendrocytes (white arrow heads: Olig2+CC1+ cells, B–E) and immature cells (white arrows: Olig2+CC1- cells, B–E). The number of Olig2+ cells and the percentage Olig2+CC1+ cells over Olig2+ cells (F) were evaluated in three independent experiments with three non-grafted mice (NG) per experiment, healthy donors (n = 8 individuals) and multiple sclerosis patients (n = 9, 3–5 grafted mice per individual). **P < 0.01, unpaired, two-tailed Student’s t-test. A second set of mice was processed for electron microscopy. Beside the mice grafted with the lymphocytes of the healthy donor subgroup (G and J), two subgroups of multiple sclerosis patients were considered (N): multiple sclerosis patients with a low (pink triangle) % of Olig-2+CC1+ (H and K, Patients 7–9) and patients with a High (purple triangle) % of Olig-2+CC1+ (I and L, Patients 1–5). Toluidine blue stained semi-thin section of lesion reveals the lesion area, delineated by a pink line (G–I). Ultrastructure analysis (J–L) was used to highlight axons remyelinated by oligodendrocytes (green), by Schwann cells (blue) or non-remyelinated (yellow) in lesions grafted with lymphocytes from the multiple sclerosis Low subgroup (n = 3, K) compared to those grafted with lymphocytes from healthy donors (n = 6, J) or the multiple sclerosis High subgroup (n = 5, L). Three to five mice were grafted for each individual. Remyelination was evaluated by measuring the total area of remyelination conducted by oligodendrocytes (M). *P < 0.05, **P < 0.01. One-way ANOVA and Tukey’s multiple comparison test. Scale bars = 100 µm in G–I; 50 µm in B–E and 5 µm in J–L.
Mentions: In nude mice, spontaneous remyelination occurs after focal demyelination from lysophosphatidylcholine (LPC) injection and is completed within 4 weeks (Jeffery and Blakemore, 1995). To evaluate how lymphocytes influence remyelination, we combined LPC-induced demyelination in the spinal cord of nude mice and the graft within the lesion 48 h after demyelination of 105 activated lymphocytes isolated from blood samples of healthy control subjects and patients with multiple sclerosis (Table 1, Supplementary Table 2 and Fig. 1A).Table 1

View Article: PubMed Central - PubMed

ABSTRACT

The factors that determine whether remyelination fails or succeeds in multiple sclerosis remain unknown. By grafting lymphocytes from patients into demyelinated lesions in mice, El Behi, Sanson et al. show that lymphocytes differ in their ability to induce remyelination. Unravelling the basis of this heterogeneity reveals prerequisites for efficient myelin repair.

No MeSH data available.


Related in: MedlinePlus