Journal
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 8, Issue 8, Pages 1396-1405Publisher
AMER SOC NEPHROLOGY
DOI: 10.2215/CJN.12931212
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Funding
- National Institute for Health Research (NIHR)
- Medical Research Council
- Academy of Medical Sciences
- Wellcome Trust
- ONE Study
- British Heart Foundation
- Kidney Patients' Association
- Guy's and St. Thomas' Charity
- NIHR Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust
- King's College London
- Medical Research Council Centre for Transplantation
- MRC [G0801537, G0500429, G0802068] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre] Funding Source: researchfish
- British Heart Foundation [RG/13/12/30395] Funding Source: researchfish
- Medical Research Council [G1000758, G0801537, MR/J006742/1, MR/K025538/1, G0500429, G0802068, G1000758B] Funding Source: researchfish
- National Institute for Health Research [CL-2008-17-003, DRF-2009-02-22] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [DRF-2009-02-22] Funding Source: National Institutes of Health Research (NIHR)
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Background and objectives Cell-based therapy with natural (CD4(+)CD25(hi)CD127(lo)) regulatory T cells to induce transplant tolerance is now technically feasible. However, regulatory T cells from hemodialysis patients awaiting transplantation may be functionally/numerically defective. Human regulatory T cells are also heterogeneous, and some are able to convert to proinflammatory Th17 cells. This study addresses the suitability of regulatory T cells from hemodialysis patients for cell-based therapy in preparation for the first clinical trials in renal transplant recipients (the ONE Study).Design, setting, participants, & measurements Healthy controls and age- and sex-matched hemodialysis patients without recent illness/autoimmune disease on established, complication-free hemodialysis for a minimum of 6 months were recruited. Circulating regulatory T cells were studied by flow cytometry to compare the regulatory T cell subpopulations. Regulatory T cells from members of each group were compared for suppressive function and plasticity (IL-17-producing capacity) before and after in vitro expansion with and without Rapamycin, using standard assays.Results Both groups had similar total regulatory T cells and subpopulations I and III. In each subpopulation, regulatory T cells expressed similar levels of the function-associated markers CD27, CD39, HLA-DR, and FOXP3. Hemodialysis regulatory T cells were less suppressive, expanded poorly compared with healthy control regulatory T cells, and produced IL-17 in the absence of Rapamycin. However, Rapamycin efficiently expanded hemodialysis regulatory T cells to a functional and stable cell product.Conclusions Rapamycin-based expansion protocols should enable clinical trials of cell-based immunotherapy for the induction of tolerance to renal allografts using hemodialysis regulatory T cells.
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