Journal
GUT
Volume 65, Issue 4, Pages 584-594Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2014-306919
Keywords
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Categories
Funding
- National Institute for Health Research [DRF/2009/02/22]
- Guy's and St Thomas' Charity [R090707, R1405170]
- Academy of Medical Sciences (Daniel Turnberg Memorial Fund)
- Medical Research Council, UK [G0802068, MR/K002996/1, G0801537/ID: 88245, MR/J006742/1]
- Wellcome Trust [WT088747MA, 091009]
- European Union 7th Framework Programme (EU FP7) [260687, 305147]
- King's Health Partners Research and Development Challenge Fund
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust
- King's College London
- National Institutes of Health Research (NIHR) [DRF-2009-02-22] Funding Source: National Institutes of Health Research (NIHR)
- British Heart Foundation [RG/13/12/30395] Funding Source: researchfish
- Crohn's & Colitis Foundation of America [504039] Funding Source: researchfish
- Medical Research Council [MR/M003493/1, G0801537, MR/L022699/1, G0802068, MR/N006445/1, MR/J006742/1, G0800746, MR/K002996/1, MR/K025538/1] Funding Source: researchfish
- National Institute for Health Research [DRF-2009-02-22] Funding Source: researchfish
- Wellcome Trust [101159/Z/13/Z] Funding Source: researchfish
- MRC [MR/K002996/1, MR/N006445/1, MR/M003493/1, MR/L022699/1, G0800746, G0802068, G0801537] Funding Source: UKRI
- Wellcome Trust [101159/Z/13/Z] Funding Source: Wellcome Trust
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Background and aim Thymus-derived regulatory T cells (T-regs) 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. T-reg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of T-regs expanded from Crohn's blood is unknown. The potential for adoptively transferred T-regs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to T-reg-mediated suppression in active CD. The capacity for expanded T-regs to home to gut and lymphoid tissue is unknown. Methods To define the optimum population for T-reg cell therapy in CD, CD4(+)CD25(+)CD127(lo)CD45RA(+) and CD4(+)CD25(+)CD127(lo)CD45RA(-)T(reg) 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 T-regs can be expanded from the blood of patients with CD to potential target dose within 22-24 days. Expanded CD45RA(+) T-regs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA(-) T-regs. CD45RA(+) T-regs highly express alpha(4)beta(7) integrin, CD62L and CC motif receptor 7 (CCR7). CD45RA(+) T-regs 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(+) T-regs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa. Conclusions CD4(+)CD25(+)CD127(lo)CD45RA(+) T-regs may be the most appropriate population from which to expand T-regs for autologous T-reg therapy for CD, paving the way for future clinical trials.
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