PMID- 19299717
OWN - NLM
STAT- MEDLINE
DCOM- 20090414
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 182
IP  - 7
DP  - 2009 Apr 1
TI  - Signal transduction inhibition of APCs diminishes th17 and Th1 responses in 
      experimental autoimmune encephalomyelitis.
PG  - 4192-9
LID - 10.4049/jimmunol.0803631 [doi]
AB  - IL-17- and IFN-gamma-secreting T cells play an important role in autoimmune 
      responses in multiple sclerosis and the model system experimental autoimmune 
      encephalomyelitis (EAE). Dendritic cells (DCs) in the periphery and microglia in 
      the CNS are responsible for cytokine polarization and expansion of this T cell 
      subset. Our results indicate that in vivo administration of a signal transduction 
      inhibitor that targets DCs to mice with EAE led to a decrease in CNS infiltration 
      of pathogenic Ag-specific T cells. Since this approach does not target T cells 
      directly, we assessed the effects on the APCs that are involved in generating the 
      T cell responses. Since in EAE and multiple sclerosis, both microglia and 
      peripheral DCs are likely to contribute to disease, we utilized a bone marrow 
      chimera system to distinguish between these two populations. These studies show 
      that peripheral DCs are the primary target but that microglia are also modestly 
      affected by CEP-701, as numbers and activation states of the cells in the CNS are 
      decreased after therapy. Our results also showed a decrease in secretion of 
      TNF-alpha, IL-6, and IL-23 by DCs as well as a decrease in expression of 
      costimulatory molecules. We further determined that levels of phospho-Stat1, 
      Stat3, Stat5, and NF-kappaB, which are signaling molecules that have been 
      implicated in these pathways, were decreased. Thus, use of this class of signal 
      transduction inhibitors may represent a novel method to treat autoimmunity by 
      dampening the autoreactive polarizing condition driven by DCs.
FAU - Skarica, Mario
AU  - Skarica M
AD  - Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins 
      University School of Medicine, Baltimore MD 21231, USA.
FAU - Wang, Tianhong
AU  - Wang T
FAU - McCadden, Erin
AU  - McCadden E
FAU - Kardian, David
AU  - Kardian D
FAU - Calabresi, Peter A
AU  - Calabresi PA
FAU - Small, Donald
AU  - Small D
FAU - Whartenby, Katharine A
AU  - Whartenby KA
LA  - eng
GR  - R01 CA090668/CA/NCI NIH HHS/United States
GR  - R01-CA11989/CA/NCI NIH HHS/United States
GR  - R01-CA70970/CA/NCI NIH HHS/United States
GR  - P01 CA070970/CA/NCI NIH HHS/United States
GR  - R37 NS041435/NS/NINDS NIH HHS/United States
GR  - NS041435/NS/NINDS NIH HHS/United States
GR  - R01 CA090668-09/CA/NCI NIH HHS/United States
GR  - R01 NS041435/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Carbazoles)
RN  - 0 (Cytokines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Furans)
RN  - 0 (Interleukin-17)
RN  - DO989GC5D1 (lestaurtinib)
RN  - EC 2.7.10.1 (Flt3 protein, mouse)
RN  - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
SB  - IM
MH  - Animals
MH  - Antigen-Presenting Cells/*drug effects/immunology
MH  - Blotting, Western
MH  - Brain/immunology/metabolism/pathology
MH  - Carbazoles/*pharmacology
MH  - Chemotaxis, Leukocyte/drug effects
MH  - Cytokines/biosynthesis/immunology
MH  - Encephalomyelitis, Autoimmune, Experimental/*drug therapy/immunology/pathology
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Furans
MH  - Interleukin-17/immunology/metabolism
MH  - Mice
MH  - Microglia/drug effects/immunology/metabolism
MH  - Signal Transduction/*drug effects/immunology
MH  - T-Lymphocyte Subsets/drug effects/immunology
MH  - Th1 Cells/*drug effects/immunology
MH  - fms-Like Tyrosine Kinase 3/deficiency/immunology
PMC - PMC3727416
MID - NIHMS250789
COIS- Disclosures The authors have no financial conflicts of interest.
EDAT- 2009/03/21 09:00
MHDA- 2009/04/15 09:00
PMCR- 2013/07/30
CRDT- 2009/03/21 09:00
PHST- 2009/03/21 09:00 [entrez]
PHST- 2009/03/21 09:00 [pubmed]
PHST- 2009/04/15 09:00 [medline]
PHST- 2013/07/30 00:00 [pmc-release]
AID - 182/7/4192 [pii]
AID - 10.4049/jimmunol.0803631 [doi]
PST - ppublish
SO  - J Immunol. 2009 Apr 1;182(7):4192-9. doi: 10.4049/jimmunol.0803631.