Synergistic immunomodulatory effects of interferon-beta1b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis.
Subcutaneous application of interferon-beta1b (IFN-beta1b) is an established therapy for patients with relapsing-remitting multiple sclerosis (RRMS), but early side effects are still a major concern. In vitro studies with myelin basic protein (MBP)-specific T-cell lines revealed a synergistic suppressive effect of IFN-beta1b and the phosphodiesterase inhibitor pentoxifylline (PTX) on proliferation and the production of tumor necrosis factor-alpha (TNF-alpha), lymphotoxin (LT), and interferon-gamma (IFN-gamma). In an initial, open labeled prospective trial, the cytokine messenger RNA (mRNA) expression of blood mononuclear cells from MS patients, receiving either IFN-beta1b alone or in combination with oral PTX, was determined by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Patients treated with IFN-beta1b alone reported more side effects during the first 3 months of treatment and had upregulated TNF-alpha as well as IFN-gamma mRNA expression during the first month, which was not detected in patients receiving both drugs. A synergistic effect of both drugs was observed on the upregulation of interleukin (IL)-10 mRNA, which was accompanied by an increase in IL-10 serum levels. Both in vitro and in vivo data suggest that co-treatment of IFN-beta1b with PTX is a promising approach to correct the disturbed cytokine balance in MS patients.
Department of Neurology, Georg-August-University of Göttingen, Germany.
F
F
Weber
T
T
Polak
A
A
Günther
B
B
Kubuschok
J
J
Janovskaja
A
A
Bitsch
S
S
Poser
P
P
Rieckmann
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007378:Interleukins / Q000097:blood; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012333:RNA, Messenger / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007378:Interleukins; D008233:Lymphotoxin-alpha; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000068576:Interferon beta-1b; D016899:Interferon-beta; D007371:Interferon-gamma; D010431:Pentoxifylline; D000068556:Interferon beta-1a