Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease

James B. Canavan, Cristiano Scottà, Anna Vossenkämper, Rimma Goldberg, Matthew J. Elder, Irit Shoval, Ellen Marks, Emilie Stolarczyk, Jonathan W. Lo, Nick Powell, Henrieta Fazekasova, Peter M. Irving, Jeremy D. Sanderson, Jane K. Howard, Simcha Yagel, Behdad Afzali, Thomas T. MacDonald, Maria P. Hernandez-Fuentes, Nahum Y. Shpigel, Giovanna LombardiGraham M. Lord*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

Background: and aim Thymus-derived regulatory T cells (Tregs) mediate dominant peripheral tolerance and treat experimental colitis. Tregs can be expanded from patient blood and were safely used in recent phase 1 studies in graft versus host disease and type 1 diabetes. Treg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of Tregs expanded from Crohn's blood is unknown. The potential for adoptively transferred Tregs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to Treg-mediated suppression in active CD. The capacity for expanded Tregs to home to gut and lymphoid tissue is unknown. Methods: To define the optimum population for Tregcell therapy in CD, CD4+CD25+CD127loCD45RA+ and CD4+CD25+CD127loCD45RA- Treg subsets were isolated from patients' blood and expanded in vitro using a workflow that can be readily transferred to a good manufacturing practice background. Results: Tregs can be expanded from the blood of patients with CD to potential target dose within 22-24 days. Expanded CD45RA+ Tregs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA- Tregs. CD45RA+ Tregs highly express α4β7 integrin, CD62L and CC motif receptor 7 (CCR7). CD45RA+ Tregs also home to human small bowel in a C.B-17 severe combined immune deficiency (SCID) xenotransplant model. Importantly, in vitro expansion enhances the suppressive ability of CD45RA+ Tregs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa. Conclusions: CD4+CD25+CD127loCD45RA+ Tregs may be the most appropriate population from which to expand Tregs for autologous Treg therapy for CD, paving the way for future clinical trials.

Original languageAmerican English
Pages (from-to)584-594
Number of pages11
JournalGut
Volume65
Issue number4
DOIs
StatePublished - Apr 2016

Bibliographical note

Funding Information:
Funding: This study was supported by grants awarded by the National Institute for Health Research (JBC, GML; grant number DRF/2009/02/22), Guy's and St Thomas' Charity (JBC, MPH-F, JDS, GML; grant number R090707), the Academy of Medical Sciences (JBC; Daniel Turnberg Memorial Fund) the Medical Research Council, UK (GML, TTM; grant number G0802068; GML, JKH, grant number MR/K002996/1; MPH-F, grant numbers G0801537/ID: 88245 and MR/J006742/1), the Wellcome Trust (NP, GML, TTM, grant number WT088747MA, GML, grant number 091009), the European Union 7th Framework Programme (EU FP7) (GLom, CS, MPH-F; The ONE study; reference 260687; MPH-F; BIO-DRIM; reference 305147) and King's Health Partners Research and Development Challenge Fund, Guy's and St Thomas' Charity (CS; grant number R1405170). Research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

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