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Kidney Int. 2018 May;93(5):1118-1130. doi: 10.1016/j.kint.2017.11.017. Epub 2018 Mar 2.

Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice.

Author information

1
Department of Biotechnology, Yonsei University College of Life Science and Biotechnology, Seoul, Republic of Korea.
2
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
3
Good T cells, Inc., Seoul, Republic of Korea.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
5
MOGAM Institute for Biomedical Research, Gyeonggi-do, Republic of Korea.
6
Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Boston, Massachusetts, USA.
7
Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
8
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: sangwonlee@yhus.ac.
9
Department of Biotechnology, Yonsei University College of Life Science and Biotechnology, Seoul, Republic of Korea; Good T cells, Inc., Seoul, Republic of Korea. Electronic address: sjrlee@yonsei.ac.kr.

Abstract

Excessive expression of Tbet and IFNγ is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet-TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall proinflammatory microenvironment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.

KEYWORDS:

T helper 1 cells; Tbet; Treg cells; inflammatory microenvironment; nucleus-transducible form; systemic lupus erythematosus

PMID:
29409726
DOI:
10.1016/j.kint.2017.11.017

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