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 journalArticlepeer-review

38 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Fingerprint Dive into the research topics of 'Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3<sup>+</sup> regulatory T cells'. Together they form a unique fingerprint.

Cite this