Combined administration of a mutant TGF-β1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance

Wensheng Zhang, Dong Zhang, Miaoda Shen, Yun Liu, Yan Tian, Angus W. Thomson, W. P.Andrew Lee, Xin Xiao Zheng

Research output: Contribution to journalArticle

Abstract

The critical roles of TGF-β in the reciprocal differentiation of tolerance-promoting CD4+Foxp3+ regulatory T cells (Tregs) and proinflammatory Th17 effector cells affect alloimmune reactivity and transplant outcome. We reasoned that a strategy to harness TGF-β and block proinflammatory cytokines would inhibit the differentiation of Th17 cells and strengthen the cadre of Tregs to promote tolerance induction and long-term allograft survival. In this study, we report the development of a long-lasting autoactive human mutant TGF-β1/Fc fusion protein that acts in conjunction with rapamycin to inhibit T cell proliferation and induce the de novo generation of Foxp3+ Treg in the periphery, while at the same time inhibiting IL-6-mediated Th17 cell differentiation. Shortterm combined treatment with TGF-β1/Fc and rapamycin achieved long-term pancreatic islet allograft survival and donorspecific tolerance in a mouse model. This effect was accompanied by expansion of Foxp3+ Tregs, enhanced alloantigen-specific Treg function, and modulation of transcript levels of Foxp3, IL-6, and IL-17. Our strategy of combined TGF-β1/Fc and rapamycin to target the IL-6-related Tregs and Th17 signaling pathways provides a promising approach for inducing transplant tolerance and its clinical application.

Original languageEnglish (US)
Pages (from-to)4750-4759
Number of pages10
JournalJournal of Immunology
Volume185
Issue number8
DOIs
StatePublished - Oct 15 2010

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Zhang, W., Zhang, D., Shen, M., Liu, Y., Tian, Y., Thomson, A. W., Lee, W. P. A., & Zheng, X. X. (2010). Combined administration of a mutant TGF-β1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance. Journal of Immunology, 185(8), 4750-4759. https://doi.org/10.4049/jimmunol.1000769