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

Jae Seung Moon, Chin Hee Mun, Jung Ho Kim, Jen Young Cho, Sung Dong Park, Tae Yoon Park, Jin Su Shin, Chun Chang Ho, Yong Beom Park, Sankar Ghosh, Alfred L.M. Bothwell, Sang Won Lee, Sang Kyou Lee

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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 pro-inflammatory micro-environment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.

Original languageEnglish
Pages (from-to)1118-1130
Number of pages13
JournalKidney International
Volume93
Issue number5
DOIs
Publication statusPublished - 2018 May

All Science Journal Classification (ASJC) codes

  • Nephrology

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    Moon, J. S., Mun, C. H., Kim, J. H., Cho, J. Y., Park, S. D., Park, T. Y., Shin, J. S., Ho, C. C., Park, Y. B., Ghosh, S., Bothwell, A. L. M., Lee, S. W., & Lee, S. K. (2018). Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. Kidney International, 93(5), 1118-1130. https://doi.org/10.1016/j.kint.2017.11.017