Time-dependent cytokine deviation toward the Th2 side in Japanese multiple sclerosis patients with interferon beta-1b

Hirofumi Ochi, Mei Feng-Jun, Manabu Osoegawa, Motozumi Minohara, Hiroyuki Murai, Takayuki Taniwaki, Jun Ichi Kira

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Abstract

To address the immune mechanism sustaining interferon beta (IFNβ) efficacy in multiple sclerosis (MS), we longitudinally analyzed expressions of IFN-γ, 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 IFNβ 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 IFNβ on individual cytokines were time-dependent and altered cytokine productions were particularly evident in CD4+ rather than CD8+ T cells. A decreased intracellular IFN-γ/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). IFNβ treatment resulted in a rapid increase in the percentage of IFN-γ- 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-γ+ 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-γ+ 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-γ+ IL-4- CD4+ T cell percentages was observed in MS patients without relapse (p<0.01). Thus, a reduction of IFN-γ+ 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-γ, 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-γ was down-regulated in the late phase of IFNβ therapy. The net effect of IFNβ on the immune balance was entirely toward type 2 immune deviation, possibly contributing to its beneficial effects on MS.

Original languageEnglish
Pages (from-to)65-73
Number of pages9
JournalJournal of the Neurological Sciences
Volume222
Issue number1-2
DOIs
Publication statusPublished - Jul 15 2004

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Interferon-beta
Multiple Sclerosis
Cytokines
T-Lymphocytes
Interleukin-4
Interleukin-13
Recurrence
Interleukin-5
Interferon beta-1b
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Time-dependent cytokine deviation toward the Th2 side in Japanese multiple sclerosis patients with interferon beta-1b. / Ochi, Hirofumi; Feng-Jun, Mei; Osoegawa, Manabu; Minohara, Motozumi; Murai, Hiroyuki; Taniwaki, Takayuki; Kira, Jun Ichi.

In: Journal of the Neurological Sciences, Vol. 222, No. 1-2, 15.07.2004, p. 65-73.

Research output: Contribution to journalArticle

Ochi, Hirofumi ; Feng-Jun, Mei ; Osoegawa, Manabu ; Minohara, Motozumi ; Murai, Hiroyuki ; Taniwaki, Takayuki ; Kira, Jun Ichi. / Time-dependent cytokine deviation toward the Th2 side in Japanese multiple sclerosis patients with interferon beta-1b. In: Journal of the Neurological Sciences. 2004 ; Vol. 222, No. 1-2. pp. 65-73.
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AU - Murai, Hiroyuki

AU - Taniwaki, Takayuki

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N2 - To address the immune mechanism sustaining interferon beta (IFNβ) efficacy in multiple sclerosis (MS), we longitudinally analyzed expressions of IFN-γ, 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 IFNβ 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 IFNβ on individual cytokines were time-dependent and altered cytokine productions were particularly evident in CD4+ rather than CD8+ T cells. A decreased intracellular IFN-γ/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). IFNβ treatment resulted in a rapid increase in the percentage of IFN-γ- 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-γ+ 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-γ+ 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-γ+ IL-4- CD4+ T cell percentages was observed in MS patients without relapse (p<0.01). Thus, a reduction of IFN-γ+ 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-γ, 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-γ was down-regulated in the late phase of IFNβ therapy. The net effect of IFNβ on the immune balance was entirely toward type 2 immune deviation, possibly contributing to its beneficial effects on MS.

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