Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3+ regulatory T cells

H. Tanaka, Weici Zhang, G. X. Yang, Y. Ando, T. Tomiyama, K. Tsuneyama, Patrick S Leung, R. L. Coppel, A. A. Ansari, Z. X. Lian, W. M. Ridgway, T. Joh, M. Eric Gershwin

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Summary: Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8+ T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice to recombination-activating gene (Rag)1-/- recipients. We then used this robust established adoptive transfer system and co-transferred CD8+ T cells from dnTGF-βRII mice with either C57BL/6 or dnTGF-βRII forkhead box protein 3 (FoxP3+) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-βRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Treg versusdnTGF-βRII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-βRII mice. Our data reflect the therapeutic potential of wild-type CD4+ FoxP3+ Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC.

Original languageEnglish (US)
Pages (from-to)253-261
Number of pages9
JournalClinical and Experimental Immunology
Volume178
Issue number2
DOIs
StatePublished - Nov 1 2014

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Forkhead Transcription Factors
Cholangitis
Adoptive Transfer
Regulatory T-Lymphocytes
Immunotherapy
T-Lymphocytes
Biliary Liver Cirrhosis
Bile Ducts
Inflammation
RAG-1 Genes
Down-Regulation
Autoimmunity
Interleukin-10
Autoimmune Diseases
Histology
Glycoproteins
transforming growth factor-beta type II receptor
Pathology
Cytokines
Therapeutics

Keywords

  • Autoimmunity
  • Cholangitis
  • Colitis
  • Murine models
  • Primary biliary cirrhosis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3+ regulatory T cells. / Tanaka, H.; Zhang, Weici; Yang, G. X.; Ando, Y.; Tomiyama, T.; Tsuneyama, K.; Leung, Patrick S; Coppel, R. L.; Ansari, A. A.; Lian, Z. X.; Ridgway, W. M.; Joh, T.; Gershwin, M. Eric.

In: Clinical and Experimental Immunology, Vol. 178, No. 2, 01.11.2014, p. 253-261.

Research output: Contribution to journalArticle

Tanaka, H, Zhang, W, Yang, GX, Ando, Y, Tomiyama, T, Tsuneyama, K, Leung, PS, Coppel, RL, Ansari, AA, Lian, ZX, Ridgway, WM, Joh, T & Gershwin, ME 2014, 'Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3+ regulatory T cells', Clinical and Experimental Immunology, vol. 178, no. 2, pp. 253-261. https://doi.org/10.1111/cei.12415
Tanaka, H. ; Zhang, Weici ; Yang, G. X. ; Ando, Y. ; Tomiyama, T. ; Tsuneyama, K. ; Leung, Patrick S ; Coppel, R. L. ; Ansari, A. A. ; Lian, Z. X. ; Ridgway, W. M. ; Joh, T. ; Gershwin, M. Eric. / Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3+ regulatory T cells. In: Clinical and Experimental Immunology. 2014 ; Vol. 178, No. 2. pp. 253-261.
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AU - Tomiyama, T.

AU - Tsuneyama, K.

AU - Leung, Patrick S

AU - Coppel, R. L.

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