Decoy receptor 3 ameliorates experimental autoimmune encephalomyelitis by directly counteracting local inflammation and downregulating Th17 cells.
To investigate the therapeutic potential of decoy receptor 3 (DcR3) in multiple sclerosis (MS), we used intrathecal (IT) administration of DcR3 into C57/BL6 mice with experimental autoimmune encephalomyelitis (EAE). DcR3 significantly ameliorated EAE symptoms as shown by a lower clinical score and less inflammation in the spinal cord. The expression of TNF-alpha, IFN-gamma, and IL-17 was lower in the spinal cord in IT DcR3-treated mice. Flow cytometry showed a drastic reduction in IL-17-producing CD4 T cells, slightly fewer IFN-gamma producing CD4 T cells and more IL-4-producing CD4 T cells isolated from the central nervous system (CNS) of IT DcR3-treated mice than of controls. Myelin oligodendrocyte glycoprotein (MOG)-specific T cell proliferation was significantly inhibited in DcR3-treated mice. The IL-17 concentration was lower and the IL-4 concentration higher in the supernatants of MOG-stimulated splenocytes from DcR3-treated mice. An adoptive transfer study showed that splenocytes from DcR3-treated mice retained this disease-inhibiting ability. Our data suggest that DcR3 has potential as a suppressor of CNS inflammation in EAE, which may be attributed to either direct inhibition of CNS inflammation or suppression of encephalitogenic Th17 cells. In conclusion, we demonstrate a therapeutic effect of DcR3 in EAE, suggesting its potential for treating human MS.
Chen
Shyi-Jou
SJ
Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
Wang
Yen-Lin
YL
Kao
Jen-Hsin
JH
Wu
Shu-Feng
SF
Lo
Wen-Tsung
WT
Wu
Chia-Cho
CC
Tao
Pao-Luh
PL
Wang
Chih-Chien
CC
Chang
Deh-Ming
DM
Sytwu
Huey-Kang
HK
D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D007278:Injections, Spinal; D051379:Mice; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D018836:Inflammation Mediators; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D011994:Recombinant Proteins; C505911:TNFRSF6B protein, human