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Immunologic and MRI markers of the therapeutic effect of IFN-β-1a in relapsing-remitting MS.

Tao Y, Zhang X, Zivadinov R, Dwyer MG, Kennedy C, Bergsland N, Ramasamy D, Durfee J, Hojnacki D, Hayward B, Dangond F, Weinstock-Guttman B, Markovic-Plese S - Neurol Neuroimmunol Neuroinflamm (2015)

Bottom Line: Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment.Findings indicate that IFN-β-1a suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination.This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-β-1a treatment in patients with RRMS.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neurology (Y.T., X.Z., S.M.-P.) and Microbiology and Immunology (S.M.-P.), University of North Carolina at Chapel Hill; Buffalo Neuroimaging Analysis Center (R.Z., M.G.D., C.K., N.B., D.R., J.D.), Department of Neurology (R.Z., M.G.D., C.K., N.B., D.R., D.H., J.D., B.W.-G.), State University of New York at Buffalo; and EMD Serono, Inc. (B.H., F.D.), Rockland, MA.

ABSTRACT

Objectives: To assess potential roles of effector cells and immunologic markers in demyelinating CNS lesion formation, and their modulation by interferon β-1a (IFN-β-1a).

Methods: Twenty-three patients with relapsing-remitting multiple sclerosis (RRMS) received IFN-β-1a for 6 months. Immunologic marker results were correlated with brain MRI lesion volumes, and volumes of normal-appearing brain tissue (NABT) with decreasing or increasing voxel-wise magnetization transfer ratio (VW-MTR), suggestive of demyelination and remyelination, respectively.

Results: Baseline expression of Th22 cell transcription factor aryl hydrocarbon receptor (AHR) and interleukin (IL)-17F, and percentages of IL-22-expressing CD4(+) and CD8(+) cells, were significantly higher in patients vs 15 healthy controls; IL-4 in CD4(+) cells was lower. Baseline percentage of IL-22-producing CD8(+) cells positively correlated with T2 lesion volumes, while percentage of IL-17A-producing CD8(+) cells positively correlated with T2 and T1 lesion volumes. IFN-β-1a induced reductions in transcription factor AHR, T-bet, and retinoic acid-related orphan nuclear hormone receptor C (RORc) gene expression, while it increased GATA3's expression in CD4(+) cells. Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment. Increased percentages of IL-10-expressing CD4(+) and CD8(+) cells correlated with greater NABT volume with increasing VW-MTR, while decreased percentage of IL-17F-expressing CD4(+) cells positively correlated with decreased NABT volume with decreasing VW-MTR.

Conclusions: Findings indicate that IFN-β-1a suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination.

Classification of evidence: This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-β-1a treatment in patients with RRMS.

No MeSH data available.


Related in: MedlinePlus

Patients with RRMS have increased Th22 and Th17 cytokine gene expression and intracellular IL-22 productionGene expression of Th22 transcription factor AHR and of IL-17F, and the percentage of IL-22–producing CD4+ and CD8+ T cells, are significantly increased in patients with RRMS in comparison with HCs, while IL-4 gene expression is decreased. (A) CD4+ T cells from 15 HCs and 23 patients with RRMS at baseline were separated using magnetic beads. Gene expression was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Horizontal bars and error bars indicate the means and SDs, respectively. (B) Fresh PBMCs derived from the same 15 HCs and 23 patients with RRMS were stimulated with PMA and ionomycin for intracellular cytokine staining. Percentages of cells expressing IL-22 in gated CD4+ and CD8+ T cells were determined by flow cytometry. Statistical analysis was performed using an unpaired t test. AHR = aryl hydrocarbon receptor; HC = healthy control; IL = interleukin; PBMC = peripheral blood mononuclear cell; RRMS = relapsing-remitting multiple sclerosis.
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Figure 1: Patients with RRMS have increased Th22 and Th17 cytokine gene expression and intracellular IL-22 productionGene expression of Th22 transcription factor AHR and of IL-17F, and the percentage of IL-22–producing CD4+ and CD8+ T cells, are significantly increased in patients with RRMS in comparison with HCs, while IL-4 gene expression is decreased. (A) CD4+ T cells from 15 HCs and 23 patients with RRMS at baseline were separated using magnetic beads. Gene expression was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Horizontal bars and error bars indicate the means and SDs, respectively. (B) Fresh PBMCs derived from the same 15 HCs and 23 patients with RRMS were stimulated with PMA and ionomycin for intracellular cytokine staining. Percentages of cells expressing IL-22 in gated CD4+ and CD8+ T cells were determined by flow cytometry. Statistical analysis was performed using an unpaired t test. AHR = aryl hydrocarbon receptor; HC = healthy control; IL = interleukin; PBMC = peripheral blood mononuclear cell; RRMS = relapsing-remitting multiple sclerosis.

Mentions: In comparison with HCs, baseline gene expression of Th22 cell transcription factor AHR was significantly increased (2.1-fold) in the CD4+ T cells of patients; IL-17F gene expression was also higher (by 1.9-fold) in CD4+ T cells from patients, while IL-4 gene expression was 3.6-fold lower (figure 1A).


Immunologic and MRI markers of the therapeutic effect of IFN-β-1a in relapsing-remitting MS.

Tao Y, Zhang X, Zivadinov R, Dwyer MG, Kennedy C, Bergsland N, Ramasamy D, Durfee J, Hojnacki D, Hayward B, Dangond F, Weinstock-Guttman B, Markovic-Plese S - Neurol Neuroimmunol Neuroinflamm (2015)

Patients with RRMS have increased Th22 and Th17 cytokine gene expression and intracellular IL-22 productionGene expression of Th22 transcription factor AHR and of IL-17F, and the percentage of IL-22–producing CD4+ and CD8+ T cells, are significantly increased in patients with RRMS in comparison with HCs, while IL-4 gene expression is decreased. (A) CD4+ T cells from 15 HCs and 23 patients with RRMS at baseline were separated using magnetic beads. Gene expression was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Horizontal bars and error bars indicate the means and SDs, respectively. (B) Fresh PBMCs derived from the same 15 HCs and 23 patients with RRMS were stimulated with PMA and ionomycin for intracellular cytokine staining. Percentages of cells expressing IL-22 in gated CD4+ and CD8+ T cells were determined by flow cytometry. Statistical analysis was performed using an unpaired t test. AHR = aryl hydrocarbon receptor; HC = healthy control; IL = interleukin; PBMC = peripheral blood mononuclear cell; RRMS = relapsing-remitting multiple sclerosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645170&req=5

Figure 1: Patients with RRMS have increased Th22 and Th17 cytokine gene expression and intracellular IL-22 productionGene expression of Th22 transcription factor AHR and of IL-17F, and the percentage of IL-22–producing CD4+ and CD8+ T cells, are significantly increased in patients with RRMS in comparison with HCs, while IL-4 gene expression is decreased. (A) CD4+ T cells from 15 HCs and 23 patients with RRMS at baseline were separated using magnetic beads. Gene expression was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Horizontal bars and error bars indicate the means and SDs, respectively. (B) Fresh PBMCs derived from the same 15 HCs and 23 patients with RRMS were stimulated with PMA and ionomycin for intracellular cytokine staining. Percentages of cells expressing IL-22 in gated CD4+ and CD8+ T cells were determined by flow cytometry. Statistical analysis was performed using an unpaired t test. AHR = aryl hydrocarbon receptor; HC = healthy control; IL = interleukin; PBMC = peripheral blood mononuclear cell; RRMS = relapsing-remitting multiple sclerosis.
Mentions: In comparison with HCs, baseline gene expression of Th22 cell transcription factor AHR was significantly increased (2.1-fold) in the CD4+ T cells of patients; IL-17F gene expression was also higher (by 1.9-fold) in CD4+ T cells from patients, while IL-4 gene expression was 3.6-fold lower (figure 1A).

Bottom Line: Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment.Findings indicate that IFN-β-1a suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination.This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-β-1a treatment in patients with RRMS.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neurology (Y.T., X.Z., S.M.-P.) and Microbiology and Immunology (S.M.-P.), University of North Carolina at Chapel Hill; Buffalo Neuroimaging Analysis Center (R.Z., M.G.D., C.K., N.B., D.R., J.D.), Department of Neurology (R.Z., M.G.D., C.K., N.B., D.R., D.H., J.D., B.W.-G.), State University of New York at Buffalo; and EMD Serono, Inc. (B.H., F.D.), Rockland, MA.

ABSTRACT

Objectives: To assess potential roles of effector cells and immunologic markers in demyelinating CNS lesion formation, and their modulation by interferon β-1a (IFN-β-1a).

Methods: Twenty-three patients with relapsing-remitting multiple sclerosis (RRMS) received IFN-β-1a for 6 months. Immunologic marker results were correlated with brain MRI lesion volumes, and volumes of normal-appearing brain tissue (NABT) with decreasing or increasing voxel-wise magnetization transfer ratio (VW-MTR), suggestive of demyelination and remyelination, respectively.

Results: Baseline expression of Th22 cell transcription factor aryl hydrocarbon receptor (AHR) and interleukin (IL)-17F, and percentages of IL-22-expressing CD4(+) and CD8(+) cells, were significantly higher in patients vs 15 healthy controls; IL-4 in CD4(+) cells was lower. Baseline percentage of IL-22-producing CD8(+) cells positively correlated with T2 lesion volumes, while percentage of IL-17A-producing CD8(+) cells positively correlated with T2 and T1 lesion volumes. IFN-β-1a induced reductions in transcription factor AHR, T-bet, and retinoic acid-related orphan nuclear hormone receptor C (RORc) gene expression, while it increased GATA3's expression in CD4(+) cells. Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment. Increased percentages of IL-10-expressing CD4(+) and CD8(+) cells correlated with greater NABT volume with increasing VW-MTR, while decreased percentage of IL-17F-expressing CD4(+) cells positively correlated with decreased NABT volume with decreasing VW-MTR.

Conclusions: Findings indicate that IFN-β-1a suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination.

Classification of evidence: This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-β-1a treatment in patients with RRMS.

No MeSH data available.


Related in: MedlinePlus