Display options
Cite
Oo YH, Ackrill S, Cole R, et al. Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis. JHEP Rep. 2019;1(4):286-296doi: 10.1016/j.jhepr.2019.08.001.
Oo, Y. H., Ackrill, S., Cole, R., Jenkins, L., Anderson, P., Jeffery, H. C., Jones, N., Jeffery, L. E., Lutz, P., Wawman, R. E., Athwal, A. K., Thompson, J., Gray, J., Guo, K., Barton, D., Hirschfield, G. M., Wong, T., Guest, P., & Adams, D. H. (2019). Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis. JHEP reports : innovation in hepatology, 1(4), 286-296. https://doi.org/10.1016/j.jhepr.2019.08.001
Oo, Ye Htun, et al. "Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis." JHEP reports : innovation in hepatology vol. 1,4 (2019): 286-296. doi: https://doi.org/10.1016/j.jhepr.2019.08.001
Oo YH, Ackrill S, Cole R, Jenkins L, Anderson P, Jeffery HC, Jones N, Jeffery LE, Lutz P, Wawman RE, Athwal AK, Thompson J, Gray J, Guo K, Barton D, Hirschfield GM, Wong T, Guest P, Adams DH. Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis. JHEP Rep. 2019 Aug 21;1(4):286-296. doi: 10.1016/j.jhepr.2019.08.001. eCollection 2019 Oct. PMID: 32039380; PMCID: PMC7001578.
Copy Download .nbib Format: NLM
Share it on

JHEP Rep. 2019 Aug 21;1(4):286-296. doi: 10.1016/j.jhepr.2019.08.001. eCollection 2019 Oct.

Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis.

JHEP reports : innovation in hepatology

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

  1. Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham.
  2. National Institute of Health Research Birmingham Biomedical Research Centre.
  3. Liver Transplant and Hepato-biliary Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom.
  4. Clinical Radiopharmacy, Imaging and Nuclear Medicine Department, University Hospital of Birmingham National Health Service Foundation Trust; Birmingham.
  5. Institute of Life Science, Swansea University Medical School, Singleton Park, Swansea.
  6. Cancer Research Clinical Trial Unit, University of Birmingham.
  7. National Health Services Blood and Transplant, Birmingham.
  8. National Institute of Health Research Wellcome Trust Clinical Research Facility, Birmingham.
  9. Department of Haematology, University Hospital Birmingham National Health Service Foundation Trust.

PMID: 32039380 PMCID: PMC7001578 DOI: 10.1016/j.jhepr.2019.08.001

Abstract

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.

© 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

Keywords: Autoimmune hepatitis; cell therapy; homing; human liver; regulatory T cells

References

  1. Gut. 2011 Dec;60(12):1611-29 - PubMed
  2. Science. 2003 Feb 14;299(5609):1057-61 - PubMed
  3. Diabetes Care. 2012 Sep;35(9):1817-20 - PubMed
  4. Front Immunol. 2016 Sep 06;7:334 - PubMed
  5. Am J Transplant. 2017 Apr;17(4):917-930 - PubMed
  6. Am J Transplant. 2017 Apr;17(4):931-943 - PubMed
  7. PLoS Med. 2016 Oct 11;13(10):e1002139 - PubMed
  8. Nature. 1993 Jan 7;361(6407):79-82 - PubMed
  9. Hepatology. 2016 Jul;64(1):138-50 - PubMed
  10. Nat Rev Immunol. 2006 Mar;6(3):244-51 - PubMed
  11. Lancet. 1997 Feb 15;349(9050):490-5 - PubMed
  12. JCI Insight. 2017 Feb 9;2(3):e89160 - PubMed
  13. J Hepatol. 2017 Apr;66(4):798-805 - PubMed
  14. Hepatology. 2013 Jan;57(1):217-27 - PubMed
  15. Hepatol Int. 2010 May 19;4(2):475-93 - PubMed
  16. J Exp Med. 2006 Jul 10;203(7):1693-700 - PubMed
  17. Sci Transl Med. 2015 Nov 25;7(315):315ra189 - PubMed
  18. J Immunol. 2010 Mar 15;184(6):2886-98 - PubMed
  19. N Engl J Med. 2011 Dec 1;365(22):2067-77 - PubMed
  20. Nat Immunol. 2005 Apr;6(4):345-52 - PubMed
  21. J Clin Invest. 2016 Apr 1;126(4):1413-24 - PubMed
  22. Clin Exp Immunol. 2017 Jun;188(3):394-411 - PubMed
  23. J Immunol. 2011 May 1;186(9):5284-93 - PubMed
  24. Gastroenterology. 2014 Aug;147(2):443-52.e5 - PubMed
  25. Clin Immunol. 2009 Oct;133(1):22-6 - PubMed
  26. J Hepatol. 2012 Nov;57(5):1044-51 - PubMed
  27. J Hepatol. 2012 Jul;57(1):125-32 - PubMed
  28. J Immunol. 1995 Aug 1;155(3):1151-64 - PubMed
  29. J Autoimmun. 2010 Feb;34(1):45-54 - PubMed
  30. Hepatology. 2007 Feb;45(2):475-85 - PubMed
  31. Immunity. 2016 Mar 15;44(3):712 - PubMed
  32. Hepatology. 2016 Aug;64(2):632-43 - PubMed
  33. Can J Gastroenterol Hepatol. 2016;2016:7181685 - PubMed
  34. Cancer Res. 2004 Nov 15;64(22):8451-5 - PubMed
  35. J Hepatol. 2014 Nov;61(5):1106-14 - PubMed
  36. Nat Med. 2016 Sep;22(9):991-3 - PubMed

Publication Types

Grant support