Abstract
Experimental autoimmune encephalomyelitis (EAE) is a T-cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis (MS). We investigated the efficacy and mechanism of immunosuppression against EAE by administering 2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride (FTY720) in Lewis rats immunized with myelin basic protein together with complete Freund's adjuvant. FTY720 treatment almost completely protected the rats against disease. The protection by FTY720 was associated with a dramatic reduction in the number of lymphocytes staining for T-cell receptors in the spinal cord as examined by immunohistochemistry. The mRNA expression of Th1 cytokines interleukin (IL)-2, IL-6, and interferon-γ in the spinal cord was also reduced dramatically as assessed by reverse-transcription polymerase chain reaction. Furthermore, lymphocytes isolated from the spleen of FTY720-treated rats were transferred into naive recipient rats against EAE manifestation by reducing both disease incidence and clinical score. These results suggested that the protective anti-inflammatory effect of treatment with FTY720 was, to a large extent, due to the inhibition of encephalitogenic T-cell responses and/or their migration into the central nervous system and may be a potential candidate for use in treating patients with MS.
Footnotes
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This study was supported by research grants from the Ministry of Health, Labor, and Welfare of Japan (12-KO-2, Millennium Project H12-Saisei-016) and a grant-in-aid (10307030) and a grant for Organized Research Combination System from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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M.F. and N.F. contributed equally to this work.
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DOI: 10.1124/jpet.102.045658
- Abbreviations:
- MS
- multiple sclerosis
- CNS
- central nervous system
- EAE
- experimental autoimmune encephalomyelitis
- CFA
- complete Freund's adjuvant
- MBP
- myelin basic protein
- Con A
- concanavalin A
- FTY720
- 2-amino-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride
- CsA
- cyclosporin A
- FK506
- tacrolimus
- IL
- interleukin
- INF-γ
- interferon-γ
- PBS
- phosphate-buffered saline
- TdT
- terminal deoxynucleotidyl transferase
- RT-PCR
- Reverse-transcription polymerase chain reaction
- bp
- base pair
- TUNUL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- S1P
- sphingosine 1-phosphate
- ISP-1
- ((2S,3R,4R)-(E)-2-3,4-dihydroxymethyl-14-oxoeicos-6-enoic acid, myriocin = thermozymocidin)
- Received October 18, 2002.
- Accepted January 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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