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
Externally publishedYes

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Transplantation Tolerance
Th17 Cells
Regulatory T-Lymphocytes
Sirolimus
Interleukin-6
Allografts
Transplants
Isoantigens
Interleukin-17
Islets of Langerhans
Cell Differentiation
Cell Proliferation
Cytokines
T-Lymphocytes
Proteins
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Combined administration of a mutant TGF-β1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance. / Zhang, Wensheng; Zhang, Dong; Shen, Miaoda; Liu, Yun; Tian, Yan; Thomson, Angus W.; Lee, W P Andrew; Zheng, Xin Xiao.

In: Journal of Immunology, Vol. 185, No. 8, 15.10.2010, p. 4750-4759.

Research output: Contribution to journalArticle

Zhang, Wensheng ; Zhang, Dong ; Shen, Miaoda ; Liu, Yun ; Tian, Yan ; Thomson, Angus W. ; Lee, W P Andrew ; Zheng, Xin Xiao. / Combined administration of a mutant TGF-β1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance. In: Journal of Immunology. 2010 ; Vol. 185, No. 8. pp. 4750-4759.
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