Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients

Objective: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)–β treatment in patients with multiple sclerosis (MS). Methods: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays. Baseline cytokine profiles were grouped by hierarchical clustering analysis. Demographic features, changes in cytokines, and clinical outcome were then assessed in the clustered patient groups. Results: A total of 157 patients were included in the study and clustered into 6 distinct subsets by baseline cytokine profiles. These subsets differed significantly in their clinical and biological response to IFN-β therapy. Two subsets were associated with patients who responded poorly to therapy. Two other subsets, associated with a good response to therapy, showed a significant reduction in relapse rates and no worsening of disability. Each subset also had differential changes in cytokine levels after 3 months of IFN-β treatment. Conclusions: There is heterogeneity in the immunologic pathways of the RRMS population, which correlates with IFN-β response.

[1]  T. Schoeb,et al.  Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis , 2015, Proceedings of the National Academy of Sciences.

[2]  B. Bernstein,et al.  Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation , 2015, Nature.

[3]  X. Montalban,et al.  NLRP3 inflammasome is associated with the response to IFN-β in patients with multiple sclerosis. , 2015, Brain : a journal of neurology.

[4]  Aaron E Miller,et al.  Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis , 2014, Multiple sclerosis.

[5]  X. Montalban,et al.  Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development , 2014, Multiple sclerosis.

[6]  D. Goodin,et al.  Interleukin 17F level and interferon β response in patients with multiple sclerosis. , 2013, JAMA neurology.

[7]  X. Montalban,et al.  Baseline Gene Expression Signatures in Monocytes from Multiple Sclerosis Patients Treated with Interferon-beta , 2013, PloS one.

[8]  J. Kira,et al.  Characteristic Cerebrospinal Fluid Cytokine/Chemokine Profiles in Neuromyelitis Optica, Relapsing Remitting or Primary Progressive Multiple Sclerosis , 2013, PloS one.

[9]  L. Steinman,et al.  Serum IL-17F does not predict poor response to IM IFNβ-1a in relapsing-remitting MS , 2012, Neurology.

[10]  Christopher D. Conrady,et al.  IFN-α-driven CCL2 Production Recruits Inflammatory Monocytes to Infection Site in Mice , 2012, Mucosal Immunology.

[11]  C. Polman,et al.  Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein , 2012, Multiple sclerosis.

[12]  C. Polman,et al.  IL-7 Promotes TH1 Development and Serum IL-7 Predicts Clinical Response to Interferon-β in Multiple Sclerosis , 2011, Science Translational Medicine.

[13]  R. Rudick,et al.  Excessive Biologic Response to IFNβ Is Associated with Poor Treatment Response in Patients with Multiple Sclerosis , 2011, PloS one.

[14]  Jacqueline A Palace,et al.  Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. , 2010, Archives of neurology.

[15]  G. Sempowski,et al.  Interleukin-7 permits Th1/Tc1 maturation and promotes ex vivo expansion of cord blood T cells: a critical step toward adoptive immunotherapy after cord blood transplantation. , 2010, Cancer research.

[16]  Bernhard Hemmer,et al.  Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis , 2010, The Lancet Neurology.

[17]  M. Mori,et al.  Different responses to interferon beta‐1b treatment in patients with neuromyelitis optica and multiple sclerosis , 2010, European journal of neurology.

[18]  J. Kolls,et al.  IL-17–Mediated Monocyte Migration Occurs Partially through CC Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Induction , 2010, The Journal of Immunology.

[19]  Lawrence Steinman,et al.  T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis , 2010, Nature Medicine.

[20]  X. Montalban,et al.  A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. , 2009, Brain : a journal of neurology.

[21]  A. Millonig,et al.  High-dose intravenous interferon beta in patients with neutralizing antibodies (HINABS): a pilot study , 2009, Multiple sclerosis.

[22]  M. Kawaguchi,et al.  Functional characterization of IL-17F as a selective neutrophil attractant in psoriasis. , 2009, The Journal of investigative dermatology.

[23]  B. Becher,et al.  IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. , 2008, The Journal of clinical investigation.

[24]  B. Müller-Myhsok,et al.  Role of the novel Th17 cytokine IL‐17F in inflammatory bowel disease (IBD): Upregulated colonic IL‐17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD , 2008, Inflammatory bowel diseases.

[25]  Pablo Villoslada,et al.  Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. , 2008, Archives of neurology.

[26]  Sergio E. Baranzini,et al.  Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets , 2008, Nature.

[27]  Kathleen M. Smith,et al.  Development, cytokine profile and function of human interleukin 17–producing helper T cells , 2007, Nature Immunology.

[28]  S. Reingold,et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria” , 2005, Annals of neurology.

[29]  M. Buttmann,et al.  Interferon-β induces transient systemic IP-10/CXCL10 chemokine release in patients with multiple sclerosis , 2004, Journal of Neuroimmunology.

[30]  R. Rudick,et al.  Defining interferon β response status in multiple sclerosis patients , 2004 .

[31]  J. Lünemann,et al.  TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis , 2003, The Lancet.

[32]  J. Parisi,et al.  Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination , 2000, Annals of neurology.

[33]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  H. Hochkeppel,et al.  The human intracellular Mx‐homologous protein is specifically induced by type I interferons , 1990, European journal of immunology.

[35]  J. Kurtzke.  Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[36]  F. Sallusto,et al.  Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. , 2007, Nature immunology.

[37]  M. Buttmann,et al.  Interferon-beta induces transient systemic IP-10/CXCL10 chemokine release in patients with multiple sclerosis. , 2004, Journal of neuroimmunology.

[38]  R. Rudick,et al.  Defining interferon beta response status in multiple sclerosis patients. , 2004, Annals of neurology.