Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment (original) (raw)

Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

, Naoko Funeshima, Yusuke Kitazawa, Hiromitsu Kimura, Hiroshi Amemiya, Seiichi Suzuki and Xiao-Kang Li

Journal of Pharmacology and Experimental Therapeutics April 2003, 305 (1) 70-77; DOI: https://doi.org/10.1124/jpet.102.045658

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

• 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.

• M.F. and N.F. contributed equally to this work.

• 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
  ((2_S_,3_R_,4_R_)-(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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