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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

Changes in immunologic markers correlate with demyelination or remyelination on brain MRIs: Baseline to 6 monthsA decrease in the percentage of IL-17–producing CD4+ cells induced by IFN-β-1a treatment correlates with decreased demyelination, while increase in the percentage of IL-10–producing CD4+ and CD8+ cells correlates with increased remyelination in NABT. Subgroup analysis was performed in 15 patients with RRMS with ≥1 relapse during the 12 months preceding study entry. (A) Patients with RRMS with active disease had flow cytometry study and 25 conventional brain MRI at baseline and 6 months after IFN-β-1a therapy. Correlation between changes in the percentage of IL-4– and IL-10–producing CD8+ cells and T2 and T1 lesion volume from baseline to 6 months posttherapy was tested using Spearman correlation test. (B) Correlation between changes in the percentage of IL-10–expressing CD4+ and CD8+ cells and increasing VW-MTR NABT volume indicating remyelination from baseline to 6 months of IFN-β-1a treatment. (C) Correlation between change in the percentage of IL-17F–expressing CD4+ T cells and NABT volume with decreasing VW-MTR indicating demyelination from baseline to 6 months. Dec = decreasing; IFN-β-1a = interferon β-1a; IL = interleukin; Inc = increasing; LV = lesion volume; NABT = normal-appearing brain tissue; RRMS = relapsing-remitting multiple sclerosis; VW-MTR = voxel-wise magnetization transfer ratio.
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Figure 5: Changes in immunologic markers correlate with demyelination or remyelination on brain MRIs: Baseline to 6 monthsA decrease in the percentage of IL-17–producing CD4+ cells induced by IFN-β-1a treatment correlates with decreased demyelination, while increase in the percentage of IL-10–producing CD4+ and CD8+ cells correlates with increased remyelination in NABT. Subgroup analysis was performed in 15 patients with RRMS with ≥1 relapse during the 12 months preceding study entry. (A) Patients with RRMS with active disease had flow cytometry study and 25 conventional brain MRI at baseline and 6 months after IFN-β-1a therapy. Correlation between changes in the percentage of IL-4– and IL-10–producing CD8+ cells and T2 and T1 lesion volume from baseline to 6 months posttherapy was tested using Spearman correlation test. (B) Correlation between changes in the percentage of IL-10–expressing CD4+ and CD8+ cells and increasing VW-MTR NABT volume indicating remyelination from baseline to 6 months of IFN-β-1a treatment. (C) Correlation between change in the percentage of IL-17F–expressing CD4+ T cells and NABT volume with decreasing VW-MTR indicating demyelination from baseline to 6 months. Dec = decreasing; IFN-β-1a = interferon β-1a; IL = interleukin; Inc = increasing; LV = lesion volume; NABT = normal-appearing brain tissue; RRMS = relapsing-remitting multiple sclerosis; VW-MTR = voxel-wise magnetization transfer ratio.

Mentions: In the subgroup of patients with active disease, an anti-inflammatory effect of IFN-β-1a, associated with increase in the percentage of IL-4–expressing CD8+ T cells, correlated with greater decrease in the volume of T2 lesions, representing the total brain lesion burden accumulated over the duration of the disease. Similarly, an increase in the percentage of IL-10+ CD8+ cells inversely correlated with hypointense T1 lesion volume, which reflects more advanced lesions characterized by axonal loss. The immunologic markers and MRI readout changes were from baseline to 6 months, as measured by conventional MRI (figure 5A). In addition, increased percentages of IL-10–producing CD4+ and CD8+ T cells correlated with greater volume of NABT with increasing VW-MTR (figure 5B), while decrease in the percentage of IL-17F–producing CD4+ T cells correlated with lower volume of NABT with decreasing VW-MTR (figure 5C).


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)

Changes in immunologic markers correlate with demyelination or remyelination on brain MRIs: Baseline to 6 monthsA decrease in the percentage of IL-17–producing CD4+ cells induced by IFN-β-1a treatment correlates with decreased demyelination, while increase in the percentage of IL-10–producing CD4+ and CD8+ cells correlates with increased remyelination in NABT. Subgroup analysis was performed in 15 patients with RRMS with ≥1 relapse during the 12 months preceding study entry. (A) Patients with RRMS with active disease had flow cytometry study and 25 conventional brain MRI at baseline and 6 months after IFN-β-1a therapy. Correlation between changes in the percentage of IL-4– and IL-10–producing CD8+ cells and T2 and T1 lesion volume from baseline to 6 months posttherapy was tested using Spearman correlation test. (B) Correlation between changes in the percentage of IL-10–expressing CD4+ and CD8+ cells and increasing VW-MTR NABT volume indicating remyelination from baseline to 6 months of IFN-β-1a treatment. (C) Correlation between change in the percentage of IL-17F–expressing CD4+ T cells and NABT volume with decreasing VW-MTR indicating demyelination from baseline to 6 months. Dec = decreasing; IFN-β-1a = interferon β-1a; IL = interleukin; Inc = increasing; LV = lesion volume; NABT = normal-appearing brain tissue; RRMS = relapsing-remitting multiple sclerosis; VW-MTR = voxel-wise magnetization transfer ratio.
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Related In: Results  -  Collection

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Figure 5: Changes in immunologic markers correlate with demyelination or remyelination on brain MRIs: Baseline to 6 monthsA decrease in the percentage of IL-17–producing CD4+ cells induced by IFN-β-1a treatment correlates with decreased demyelination, while increase in the percentage of IL-10–producing CD4+ and CD8+ cells correlates with increased remyelination in NABT. Subgroup analysis was performed in 15 patients with RRMS with ≥1 relapse during the 12 months preceding study entry. (A) Patients with RRMS with active disease had flow cytometry study and 25 conventional brain MRI at baseline and 6 months after IFN-β-1a therapy. Correlation between changes in the percentage of IL-4– and IL-10–producing CD8+ cells and T2 and T1 lesion volume from baseline to 6 months posttherapy was tested using Spearman correlation test. (B) Correlation between changes in the percentage of IL-10–expressing CD4+ and CD8+ cells and increasing VW-MTR NABT volume indicating remyelination from baseline to 6 months of IFN-β-1a treatment. (C) Correlation between change in the percentage of IL-17F–expressing CD4+ T cells and NABT volume with decreasing VW-MTR indicating demyelination from baseline to 6 months. Dec = decreasing; IFN-β-1a = interferon β-1a; IL = interleukin; Inc = increasing; LV = lesion volume; NABT = normal-appearing brain tissue; RRMS = relapsing-remitting multiple sclerosis; VW-MTR = voxel-wise magnetization transfer ratio.
Mentions: In the subgroup of patients with active disease, an anti-inflammatory effect of IFN-β-1a, associated with increase in the percentage of IL-4–expressing CD8+ T cells, correlated with greater decrease in the volume of T2 lesions, representing the total brain lesion burden accumulated over the duration of the disease. Similarly, an increase in the percentage of IL-10+ CD8+ cells inversely correlated with hypointense T1 lesion volume, which reflects more advanced lesions characterized by axonal loss. The immunologic markers and MRI readout changes were from baseline to 6 months, as measured by conventional MRI (figure 5A). In addition, increased percentages of IL-10–producing CD4+ and CD8+ T cells correlated with greater volume of NABT with increasing VW-MTR (figure 5B), while decrease in the percentage of IL-17F–producing CD4+ T cells correlated with lower volume of NABT with decreasing VW-MTR (figure 5C).

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