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

ABSTRACT: To assess potential roles of effector cells and immunologic markers in demyelinating CNS lesion formation, and their modulation by interferon ?-1a (IFN-?-1a).Twenty-three patients with relapsing-remitting multiple sclerosis (RRMS) received IFN-?-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.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-?-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.Findings indicate that IFN-?-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-?-1a treatment in patients with RRMS.

SUBMITTER: Tao Y

PROVIDER: S-EPMC4645170 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Tao Yazhong Y Zhang Xin X Zivadinov Robert R Dwyer Michael G MG Kennedy Cheryl C Bergsland Niels N Ramasamy Deepa D Durfee Jacqueline J Hojnacki David D Hayward Brooke B Dangond Fernando F Weinstock-Guttman Bianca B Markovic-Plese Silva S

Neurology(R) neuroimmunology & neuroinflammation 20151112 6

<h4>Objectives</h4>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).<h4>Methods</h4>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-MT ...[more]

PMID: 26601116

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Project description:One of our new major finding among the genes that contributes to MS susceptibility is ICSBP1. The so called disease modifying therapies like interferon-beta (IFN-β), possibly acting on the peripheral T-cells, reduce the disease activity and the clinical progression, with a MRI-detectable effect in preventing lesion burden and cerebral atrophy development in RR-MS. It suggests a critical role of peripheral blood mononuclear cells (PBMCs) immune response and modulation in developing inflammation in the brain. We tested the hypothesis that the genetic effect of the susceptible allele ICSBP1 can impact the gene expression profile of molecules belonging to the interferon pathway. We therefore interrogated the PBMC for changes in gene expression profile. We correlate those changes with the minor allele frequency for ICSBP1, performing independent quantitative trait analysis for each treatment category. Expression Quantitative Trait Loci Association with a p value < 0.05 have been used in follow up analysis. The regression coefficient of the Quantitative trait association represents the degree of correlation between the gene expression for each interrogated target gene and the minor allele frequency of the SNP for our gene of interest. This coefficient has been used as input in the subsequent Gene Set Enrichment Analysis performed in a pre-ranked approach. The resulting GSEA-SNP method rests on the assumption that SNPs underlying a disease phenotype might affect genes constituting a signaling pathway or genes with a common regulation. Therefore, GSEA-SNP can facilitate the identification of pathways or of underlying biological mechanisms. We used microarrays to capture gene expression profile of untreated subjects and of subjects under disease modyfing treatment (Interferon Beta and Glatiramer Acetate), in order to correlate gene expression and genotype data and in order to identify sets of genes specifically regulated in the different treatment categories.

Project description:ObjectiveTo characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.MethodsComparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.ResultsAlemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.ConclusionsIn patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.Classification of evidenceThis study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.

Project description:Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1.RRMS patients (18-65 years; Expanded Disability Status Scale score ?5) were randomized to double-blind placebo or peginterferon beta-1a 125 ?g every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted.1512 patients were randomized and dosed (placebo n?=?500; peginterferon beta-1a every 2 [n?=?512] or 4 [n?=?500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p?<?0.0001. Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p?<?0.0001), as well as the volume of T2 and T1 lesions (p?<?0.05) at Weeks 24 and 48. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p?<?0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen when allowing for minimal MRI activity.During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders.ClinicalTrials.gov: NCT00906399.

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

Publications

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

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