期刊
PLOS ONE
卷 9, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0090387
关键词
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资金
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- National Institute for Health Research (NIHR) Biomedical Research Centre based at King's College London
- Guy's and St Thomas' Charity Trust [R070723]
- Medical Research Council in the UK [MR/J006742/1]
- British Heart Foundation in the UK [RG/08/005/25303]
- MRC [G0801965] Funding Source: UKRI
- British Heart Foundation [RG/13/12/30395, RG/08/005/25303] Funding Source: researchfish
- Medical Research Council [MR/J006742/1, G0801965] Funding Source: researchfish
Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting beta cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2r gamma(null) mice with cord blood-derived human CD34(+) stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human T-regs. Mechanistically, T-regs inhibited the infiltration of innate immune cells and CD4(+) T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for T-reg therapy to control human islet rejection. We also show for the first time that CD34(+) cells-reconstituted NOD-scid IL2r gamma(null) mouse model could be beneficial for investigating human innate immunity in vivo.
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