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RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells.

Authors
 Tae Yoon Park  ;  Sung Dong Park  ;  Jen Young Cho  ;  Jae Seung Moon  ;  Na Yeon Kim  ;  Kyungsoo Park  ;  Rho Hyun Seong  ;  Sang Won Lee  ;  Tomohiro Morio  ;  Alfred L. M. Bothwell  ;  Sang Kyou Lee 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.111(52) : 18673-18678, 2014 
Journal Title
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 
ISSN
 0027-8424 
Issue Date
2014
MeSH
Animals ; Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/immunology* ; Arthritis, Rheumatoid/pathology ; Arthritis, Rheumatoid/therapy ; Cell Differentiation/genetics ; Cell Differentiation/immunology* ; Cell Nucleus/immunology* ; Cell Nucleus/pathology ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Encephalomyelitis, Autoimmune, Experimental/immunology* ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Encephalomyelitis, Autoimmune, Experimental/therapy ; HEK293 Cells ; HeLa Cells ; Humans ; Mice ; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics ; Nuclear Receptor Subfamily 1, Group F, Member 3/immunology* ; Spinal Cord/immunology ; Spinal Cord/pathology ; Th1 Cells/immunology ; Th1 Cells/pathology ; Th17 Cells/immunology* ; Th17 Cells/pathology
Keywords
RORγt ; TH17 ; TMD ; autoimmunity ; transcription factor
Abstract
The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to TH17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited TH17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into TH17, but not into TH1, TH2, or Treg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4(+) T cells and spinal cord-infiltrating CD4(+) T cells, and suppress the functions of TH17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4(+) IL-17(+) T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking TH1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.
Files in This Item:
T201405448.pdf Download
DOI
10.1073/pnas.1413687112
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Sang Won(이상원) ORCID logo https://orcid.org/0000-0002-8038-3341
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/138672
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