The complexicity of cytokine treatment in ongoing EAE induced with MBP peptide 68-86 in Lewis rats.
IL-10 and TGF-beta1 are important immunoregulatory cytokines associated with clinical remissions in multiple sclerosis and amelioration of experimental allergic encephalomyelitis (EAE). IL-10 and TGF-beta1 have previously been shown to prevent the development of EAE. Here, we study effects of IL-10 and TGF-beta1 in ongoing EAE. When IL-10 or TGF-beta1 was administered by the nasal route from day 0 to day 7 postimmunization (pi), both IL-10 and TGF-beta1 prevented the development of acute EAE in Lewis rats. When IL-10 or TGF-beta1 was administered by the nasal route from day 5 to day 12 pi, both IL-10 and TGF-beta1 failed to influence clinical EAE. The inhibition of clinical EAE severity in IL-10-prevented rats was associated with reduced proliferation, IFN-gamma mRNA expression, and IFN-gamma secretion, while proliferation as well as IFN-gamma mRNA expression and secretion were augmented in TGF-beta1-prevented rats. TGF-beta1-prevented rats exhibited high levels of NO production by DC, which may mediate apoptosis of CD4+ T cells and of the DC themselves. For prevention, both IL-10 and TGF-beta1 inhibited infiltration of CD4+ T cells within the CNS, but neither IL-10 nor TGF-beta1 induced immune deviation from Th1 to Th2. Expression of IL-4 mRNA was not altered in IL-10- and TGF-beta1-prevented rats. These results demonstrate that IL-10 and TGF-beta administration by the nasal route can prevent the development of acute EAE, but by different mechanisms. The findings in rats with ongoing EAE have implications for the clinical application of cytokine treatment in autoimmune diseases.
Xu
L Y
LY
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Ishikawa
M
M
Huang
Y M
YM
Levi
M
M
van der Meide
P H
PH
Wahren
B
B
Link
H
H
Xiao
B G
BG
D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D003713:Dendritic Cells / Q000276:immunology; D004333:Drug Administration Routes; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D004676:Myelin Basic Protein / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000627:therapeutic use*
D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C110235:myelin basic protein 68-86; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma