Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
Ye Htun Oo,
Susan Ackrill,
Richard Cole,
Lee Jenkins,
Philip Anderson,
Hannah C. Jeffery,
Nicholas Jones,
Louisa E. Jeffery,
Philipp Lutz,
Rebecca E. Wawman,
Amrita Kaur Athwal,
Jacqui Thompson,
Joanna Gray,
Kathy Guo,
Darren Barton,
Gideon M Hirschfield,
Timothy Wong,
Peter Guest,
David H. Adams
Affiliations
Ye Htun Oo
Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham; National Institute of Health Research Birmingham Biomedical Research Centre; Liver Transplant and Hepato-biliary Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom; Corresponding authors. Addresses: Dr Ye Htun Oo, Consultant Hepatologist & Clinician Scientist, Room 540, 5th Floor, Institute of Biomedical Research, Centre for Liver Research and Birmingham National Institute of Health Research Inflammation Biomedical Research Centre, University of Birmingham., Liver Unit, University Hospital Birmingham NHS Foundation Trust, Vincent Drive, B15 2TT, Birmingham, UK. Tel.: +44 121 414 2246; fax:+44 121 415 8701, and Professor David H. Adams, Pro-Vice Chancellor, Head of College of Medical and Dental Sciences, Dean of Medicine, Director of Birmingham National Institute of Health Research Inflammation Biomedical Research Centre, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, Liver Unit, University Hospital Birmingham NHS Foundation Trust, Vincent Drive, B15 2TT, Birmingham, UK. Tel.: +44 121 4143780.
Susan Ackrill
Clinical Radiopharmacy, Imaging and Nuclear Medicine Department, University Hospital of Birmingham National Health Service Foundation Trust; Birmingham
Richard Cole
Clinical Radiopharmacy, Imaging and Nuclear Medicine Department, University Hospital of Birmingham National Health Service Foundation Trust; Birmingham
Lee Jenkins
Clinical Radiopharmacy, Imaging and Nuclear Medicine Department, University Hospital of Birmingham National Health Service Foundation Trust; Birmingham
Philip Anderson
Clinical Radiopharmacy, Imaging and Nuclear Medicine Department, University Hospital of Birmingham National Health Service Foundation Trust; Birmingham
Hannah C. Jeffery
Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham
Nicholas Jones
Institute of Life Science, Swansea University Medical School, Singleton Park, Swansea
Louisa E. Jeffery
Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham
Philipp Lutz
Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham
Rebecca E. Wawman
Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham
Amrita Kaur Athwal
Cancer Research Clinical Trial Unit, University of Birmingham
Jacqui Thompson
National Health Services Blood and Transplant, Birmingham
Joanna Gray
National Institute of Health Research Wellcome Trust Clinical Research Facility, Birmingham
Kathy Guo
National Institute of Health Research Birmingham Biomedical Research Centre; Department of Haematology, University Hospital Birmingham National Health Service Foundation Trust
Darren Barton
Cancer Research Clinical Trial Unit, University of Birmingham
Gideon M Hirschfield
Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham; National Institute of Health Research Birmingham Biomedical Research Centre
Timothy Wong
Department of Haematology, University Hospital Birmingham National Health Service Foundation Trust
Peter Guest
Clinical Radiopharmacy, Imaging and Nuclear Medicine Department, University Hospital of Birmingham National Health Service Foundation Trust; Birmingham
David H. Adams
Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham; National Institute of Health Research Birmingham Biomedical Research Centre; Liver Transplant and Hepato-biliary Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom; Corresponding authors. Addresses: Dr Ye Htun Oo, Consultant Hepatologist & Clinician Scientist, Room 540, 5th Floor, Institute of Biomedical Research, Centre for Liver Research and Birmingham National Institute of Health Research Inflammation Biomedical Research Centre, University of Birmingham., Liver Unit, University Hospital Birmingham NHS Foundation Trust, Vincent Drive, B15 2TT, Birmingham, UK. Tel.: +44 121 414 2246; fax:+44 121 415 8701, and Professor David H. Adams, Pro-Vice Chancellor, Head of College of Medical and Dental Sciences, Dean of Medicine, Director of Birmingham National Institute of Health Research Inflammation Biomedical Research Centre, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, Liver Unit, University Hospital Birmingham NHS Foundation Trust, Vincent Drive, B15 2TT, Birmingham, UK. Tel.: +44 121 4143780.
Background & Aims: Autoimmune hepatitis (AIH) is an immune-mediated disease with no curative treatment. Regulatory T cell (Treg) therapy is potentially curative in AIH given the critical role of Tregs in preventing autoimmunity. To work effectively, adoptively transferred Tregs must migrate to and survive within the inflamed liver. We conducted a proof-of-concept study aiming to assess the safety and liver-homing properties of good manufacturing practice (GMP)-grade autologous Tregs in patients with AIH. Methods: Autologous polyclonal GMP-grade Tregs were isolated using leukapheresis and CliniMACS, labelled with indium tropolonate and re-infused intravenously to 4 patients with AIH. GMP-Treg homing to the liver was investigated with longitudinal gamma camera and SPECT-CT scanning. GMP-Treg immunophenotype, function and immunometabolic state were assessed during the study. Results: We observed that the isolated Tregs were suppressive and expressed CXCR3, a chemokine receptor involved in recruitment into the inflamed liver, as well as Treg functional markers CD39, CTLA-4 and the transcription factor Foxp3. Serial gamma camera and SPECT-CT imaging demonstrated that 22–44% of infused Tregs homed to and were retained in the livers of patients with autoimmune hepatitis for up to 72 h. The infused cells did not localise to any off-target organs other than the spleen and bone marrow. GMP-Tregs were metabolically competent and there were no infusion reactions or high-grade adverse effects after Treg infusion. Conclusion: Our novel findings suggest that the liver is a good target organ for Treg cellular therapy, supporting the development of clinical trials to test efficacy in autoimmune hepatitis and other autoimmune liver diseases. Lay summary: Autoimmune liver diseases occur when the body’s immune cells target their own liver cells. Regulatory T cells (Tregs) prevent autoimmunity, thus they are a potential therapy for autoimmune liver diseases. In patients with autoimmune hepatitis, Treg infusion is safe, with nearly a quarter of infused Tregs homing to the liver and suppressing tissue-damaging effector T cells. Thus, Tregs are a potentially curative immune cell therapy for early autoimmune liver diseases. Keywords: Autoimmune hepatitis, regulatory T cells, human liver, homing, cell therapy
