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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

IFN-β-1a treatment inhibits expression of Th22- and Th17-related genes in CD4+ cellsIFN-β-1a treatment of patients with RRMS inhibited Th22, Th1, and Th17, while inducing Th2 cell-related gene expression in CD4+ T cells. CD4+ T cells from 21 patients with RRMS at baseline and month 6 after IFN-β-1a treatment were separated using magnetic beads. Gene expression of (A) transcription factors, (B) cytokines, and (C) cytokine receptors was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Statistical analysis was performed using a paired t test. AHR = aryl hydrocarbon receptor; IFN-β-1a = interferon β-1a; IL = interleukin; RORc = retinoic acid–related orphan nuclear hormone receptor C; RRMS = relapsing-remitting multiple sclerosis.
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Figure 3: IFN-β-1a treatment inhibits expression of Th22- and Th17-related genes in CD4+ cellsIFN-β-1a treatment of patients with RRMS inhibited Th22, Th1, and Th17, while inducing Th2 cell-related gene expression in CD4+ T cells. CD4+ T cells from 21 patients with RRMS at baseline and month 6 after IFN-β-1a treatment were separated using magnetic beads. Gene expression of (A) transcription factors, (B) cytokines, and (C) cytokine receptors was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Statistical analysis was performed using a paired t test. AHR = aryl hydrocarbon receptor; IFN-β-1a = interferon β-1a; IL = interleukin; RORc = retinoic acid–related orphan nuclear hormone receptor C; RRMS = relapsing-remitting multiple sclerosis.

Mentions: After 6 months of treatment with IFN-β-1a, significant reductions were observed in CD4+ T cell gene expression of Th22 transcription factor AHR (2.2-fold), Th1 transcription factor T-bet (1.9-fold), and Th17 transcription factor RORc (1.6-fold), whereas expression of Th2 transcription factor GATA3 was significantly increased compared with baseline (2.9-fold; figure 3A).


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)

IFN-β-1a treatment inhibits expression of Th22- and Th17-related genes in CD4+ cellsIFN-β-1a treatment of patients with RRMS inhibited Th22, Th1, and Th17, while inducing Th2 cell-related gene expression in CD4+ T cells. CD4+ T cells from 21 patients with RRMS at baseline and month 6 after IFN-β-1a treatment were separated using magnetic beads. Gene expression of (A) transcription factors, (B) cytokines, and (C) cytokine receptors was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Statistical analysis was performed using a paired t test. AHR = aryl hydrocarbon receptor; IFN-β-1a = interferon β-1a; IL = interleukin; RORc = retinoic acid–related orphan nuclear hormone receptor C; RRMS = relapsing-remitting multiple sclerosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: IFN-β-1a treatment inhibits expression of Th22- and Th17-related genes in CD4+ cellsIFN-β-1a treatment of patients with RRMS inhibited Th22, Th1, and Th17, while inducing Th2 cell-related gene expression in CD4+ T cells. CD4+ T cells from 21 patients with RRMS at baseline and month 6 after IFN-β-1a treatment were separated using magnetic beads. Gene expression of (A) transcription factors, (B) cytokines, and (C) cytokine receptors was measured using quantitative real time–PCR. Results are expressed as the relative gene expression normalized against 18S messenger RNA. Statistical analysis was performed using a paired t test. AHR = aryl hydrocarbon receptor; IFN-β-1a = interferon β-1a; IL = interleukin; RORc = retinoic acid–related orphan nuclear hormone receptor C; RRMS = relapsing-remitting multiple sclerosis.
Mentions: After 6 months of treatment with IFN-β-1a, significant reductions were observed in CD4+ T cell gene expression of Th22 transcription factor AHR (2.2-fold), Th1 transcription factor T-bet (1.9-fold), and Th17 transcription factor RORc (1.6-fold), whereas expression of Th2 transcription factor GATA3 was significantly increased compared with baseline (2.9-fold; figure 3A).

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