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Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
,
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
JHEP Reports, Volume: 1, Issue: 4, Pages: 286 - 296
Swansea University Author:
Nick Jones
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DOI (Published version): 10.1016/j.jhepr.2019.08.001
Abstract
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 a...
| Published in: | JHEP Reports |
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| ISSN: | 2589-5559 |
| Published: |
Elsevier BV
2019
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa52812 |
| Abstract: |
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. |
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| Keywords: |
Autoimmune hepatitis; regulatory T cells; human liver; homing; cell therapy |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This Research was funded by 1) Medical Research Council Clinician Scientist Grant (G1002552); 2) Sir Jules Thorn Trust Biomedical Research Award; 3) National Institute of Health Research Liver Biomedical Research Unit, and 4) Queen Elizabeth Hospital Birmingham Charity. |
| Issue: |
4 |
| Start Page: |
286 |
| End Page: |
296 |