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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, Nick Jones Orcid Logo, 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 Orcid Logo

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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...

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Published in: JHEP Reports
ISSN: 2589-5559
Published: Elsevier BV 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa52812
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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&#x2013;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.</abstract><type>Journal Article</type><journal>JHEP Reports</journal><volume>1</volume><journalNumber>4</journalNumber><paginationStart>286</paginationStart><paginationEnd>296</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2589-5559</issnElectronic><keywords>Autoimmune hepatitis; regulatory T cells; human liver; homing; cell therapy</keywords><publishedDay>1</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-10-01</publishedDate><doi>10.1016/j.jhepr.2019.08.001</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><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.</funders><projectreference/><lastEdited>2025-04-28T13:27:00.7489343</lastEdited><Created>2019-11-21T09:18:40.3811881</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Ye Htun</firstname><surname>Oo</surname><order>1</order></author><author><firstname>Susan</firstname><surname>Ackrill</surname><order>2</order></author><author><firstname>Richard</firstname><surname>Cole</surname><order>3</order></author><author><firstname>Lee</firstname><surname>Jenkins</surname><order>4</order></author><author><firstname>Philip</firstname><surname>Anderson</surname><order>5</order></author><author><firstname>Hannah C.</firstname><surname>Jeffery</surname><order>6</order></author><author><firstname>Nick</firstname><surname>Jones</surname><orcid>0000-0003-4846-5117</orcid><order>7</order></author><author><firstname>Louisa E.</firstname><surname>Jeffery</surname><order>8</order></author><author><firstname>Philipp</firstname><surname>Lutz</surname><order>9</order></author><author><firstname>Rebecca E.</firstname><surname>Wawman</surname><order>10</order></author><author><firstname>Amrita Kaur</firstname><surname>Athwal</surname><order>11</order></author><author><firstname>Jacqui</firstname><surname>Thompson</surname><order>12</order></author><author><firstname>Joanna</firstname><surname>Gray</surname><order>13</order></author><author><firstname>Kathy</firstname><surname>Guo</surname><order>14</order></author><author><firstname>Darren</firstname><surname>Barton</surname><order>15</order></author><author><firstname>Gideon M</firstname><surname>Hirschfield</surname><order>16</order></author><author><firstname>Timothy</firstname><surname>Wong</surname><order>17</order></author><author><firstname>Peter</firstname><surname>Guest</surname><order>18</order></author><author><firstname>David H.</firstname><surname>Adams</surname><order>19</order></author></authors><documents><document><filename>52812__16399__a6e9bbde7c144ff5becff1108c2ceacb.pdf</filename><originalFilename>52812.pdf</originalFilename><uploaded>2020-01-23T12:41:15.4464947</uploaded><type>Output</type><contentLength>1596377</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>Distributed under the terms of a Creative Commons CC BY-NC-ND Licence.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by-nc-nd/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling 2025-04-28T13:27:00.7489343 v2 52812 2019-11-21 Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 2019-11-21 MEDS 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. Journal Article JHEP Reports 1 4 286 296 Elsevier BV 2589-5559 Autoimmune hepatitis; regulatory T cells; human liver; homing; cell therapy 1 10 2019 2019-10-01 10.1016/j.jhepr.2019.08.001 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee 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. 2025-04-28T13:27:00.7489343 2019-11-21T09:18:40.3811881 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Ye Htun Oo 1 Susan Ackrill 2 Richard Cole 3 Lee Jenkins 4 Philip Anderson 5 Hannah C. Jeffery 6 Nick Jones 0000-0003-4846-5117 7 Louisa E. Jeffery 8 Philipp Lutz 9 Rebecca E. Wawman 10 Amrita Kaur Athwal 11 Jacqui Thompson 12 Joanna Gray 13 Kathy Guo 14 Darren Barton 15 Gideon M Hirschfield 16 Timothy Wong 17 Peter Guest 18 David H. Adams 19 52812__16399__a6e9bbde7c144ff5becff1108c2ceacb.pdf 52812.pdf 2020-01-23T12:41:15.4464947 Output 1596377 application/pdf Version of Record true Distributed under the terms of a Creative Commons CC BY-NC-ND Licence. true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
spellingShingle Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
Nick Jones
title_short Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
title_full Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
title_fullStr Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
title_full_unstemmed Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
title_sort Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis
author_id_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744
author_id_fullname_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones
author Nick Jones
author2 Ye Htun Oo
Susan Ackrill
Richard Cole
Lee Jenkins
Philip Anderson
Hannah C. Jeffery
Nick 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
format Journal article
container_title JHEP Reports
container_volume 1
container_issue 4
container_start_page 286
publishDate 2019
institution Swansea University
issn 2589-5559
doi_str_mv 10.1016/j.jhepr.2019.08.001
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description 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.
published_date 2019-10-01T04:43:32Z
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