title: Time-dependent cytokine deviation toward the Th2 side in Japanese multiple sclerosis patients with interferon beta-1b.
abstract: To address the immune mechanism sustaining interferon beta (IFNbeta) efficacy in multiple sclerosis (MS), we longitudinally analyzed expressions of IFN-gamma, IL-4, IL-5 and IL-13 in CD4+ T cells and CD8+ T cells in 22 Japanese MS patients (16 patients with conventional MS and 6 with opticospinal MS) undergoing IFNbeta using flow cytometry. During the 48-week observation period, five opticospinal MS patients (83%) relapsed compared to only four conventional MS patients (25%); the frequency of relapsed patients was significantly higher in the former (p=0.046). The effects of IFNbeta on individual cytokines were time-dependent and altered cytokine productions were particularly evident in CD4+ rather than CD8+ T cells. A decreased intracellular IFN-gamma/IL-4 ratio in CD4+ T cells was thus evident soon after the initiation of therapy, and persisted for the entire 1 year follow-up period, regardless of whether or not the patient relapsed (p<0.01). IFNbeta treatment resulted in a rapid increase in the percentage of IFN-gamma- IL-4+ and IL-13+ CD4+ T cells 1 week after the initiation of therapy and high values were sustained for 6 months but declined to the baseline over 1 year. Later, the percentage of IFN-gamma+ IL-4- CD4+ T cells decreased significantly from weeks 24 through 48 of therapy (p<0.01). When comparisons with the pretreatment values were made for each subtype of MS, a significant reduction of IFN-gamma+ IL-4- CD4+ T cell percentages was shown in conventional MS (p<0.0001), but not in opticospinal MS. Moreover, when such a comparison was made by the presence or absence of relapse during therapy, a significant reduction of IFN-gamma+ IL-4- CD4+ T cell percentages was observed in MS patients without relapse (p<0.01). Thus, a reduction of IFN-gamma+ IL-4- CD4+ T cell percentages in the late phase of therapy is considered important for reducing relapse in conventional MS. When the expression patterns of IFN-gamma, IL-4, IL-5 and IL-13 in CD4+ T cells and CD8+ T cells were compared between patients with and without relapse during therapy, the only significant difference was an increase in the IL-13+ CD4+ T cell percentages in patients with relapse compared to those without (p<0.05). The results indicate that in CD4+ T cells IL-4 was preferentially up-regulated in the early course and IFN-gamma was down-regulated in the late phase of IFNbeta therapy. The net effect of IFNbeta on the immune balance was entirely toward type 2 immune deviation, possibly contributing to its beneficial effects on MS.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ochi
authors.forename: Mei
authors.initials: M
authors.lastname: Feng-Jun
authors.forename: Manabu
authors.initials: M
authors.lastname: Osoegawa
authors.forename: Motozumi
authors.initials: M
authors.lastname: Minohara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Murai
authors.forename: Takayuki
authors.initials: T
authors.lastname: Taniwaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D012008:Recurrence; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D018793:Interleukin-13; D015848:Interleukin-5; D000068576:Interferon beta-1b; D015847:Interleukin-4; D016899:Interferon-beta; D007371:Interferon-gamma