In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 52 ( 2014-12-30), p. 18673-18678
Abstract:
The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to T H 17 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 T H 17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into T H 17, but not into T H 1, T H 2, or T reg 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 T H 17 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 T H 1 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 T H 17 or T H 1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1413687112
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2014
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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