Long-term favorable response to interferon beta-1b is linked to cytokine deviation toward the Th2 and Tc2 sides in Japanese patients with multiple sclerosis.
To address the immune mechanism of the long-term beneficial effects of interferon beta (IFN-beta), we measured the intracellular cytokine production patterns of IFN-gamma, IL-4 and IL-13 in peripheral blood CD4+ and CD8+ T cells, which previously displayed alterations during the early course of IFN-beta treatment, in 15 Japanese patients after long-term IFN-beta administration. The patients were treated with IFN-beta-1b 8 x 10(6) units given subcutaneously every other day for a mean period of 34.5 +/- 5.5 months (range: 26-43 months). During the follow-up period, 6 patients experienced 33 relapses, while the other 9 were relapse-free. The results revealed the following cytokine alterations: (1) type 2 cytokine, such as IL-4 and IL-13, were significantly increased in producing cell percentages in both CD4+ (p = 0.0356 and p = 0.0007, respectively) and CD8+ (p = 0.0231 and p = 0.0170, respectively) T cells while IFN-gamma, a representative type 1 cytokine, was significantly decreased in the absolute producing cell numbers (p = 0.0125 in CD4+ T cells and p = 0.0022 in CD8+ T cells) even after approximately 3 years of IFN-beta administration; (2) the intracellular IFN-gamma / IL-4 ratio tended to decrease in both CD4+ and CD8+ T cells (p = 0.0535 and p = 0.0783, respectively), reflecting a strong downmodulation of type 1 cytokine producing cells; and importantly (3) alterations such as the decreased intracellular IFN-gamma / IL-4 ratio in CD4+ T cells and increased percentage of CD8+ IL-13+ T cells compared with the pretreatment levels were only statistically significant in MS patients without relapse during IFN-beta therapy (p = 0.0152 and p = 0.0078, respectively). Therefore, we consider that cytokine deviation toward the Th2 and Tc2 sides is linked to a long-term favorable response to IFN-beta, while a higher intracellular IFN-gamma / IL-4 ratio is associated with treatment failure.
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Feng-Jun
FJ
Mei
Manabu
M
Osoegawa
Hirofumi
H
Ochi
Motozumi
M
Minohara
Shi
S
Nan
Hiroyuki
H
Murai
Takaaki
T
Ishizu
Takayuki
T
Taniwaki
Jun-ichi
J
Kira
D000328:Adult; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000378:metabolism; D011237:Predictive Value of Tests; D012008:Recurrence; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D016896:Treatment Outcome
D015415:Biomarkers; D016207:Cytokines; D000068576:Interferon beta-1b; D016899:Interferon-beta