title: Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.
abstract: Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β 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 IL2rγnull 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 Tregs. Mechanistically, Tregs 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 Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.
authors.affiliation: Medical Research Council (MRC) for Transplantation, King's College London, London, United Kingdom.
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Medical Research Council (MRC) for Transplantation, King's College London, London, United Kingdom.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Diabetes & Endocrinology, King's College London, London, United Kingdom.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Diabetes & Endocrinology, King's College London, London, United Kingdom.
authors.forename: Guocai
authors.initials: G
authors.lastname: Huang
authors.affiliation: Medical Research Council (MRC) for Transplantation, King's College London, London, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mirenda
authors.affiliation: Medical Research Council (MRC) for Transplantation, King's College London, London, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Dorling
authors.affiliation: Medical Research Council (MRC) for Transplantation, King's College London, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Lechler
authors.affiliation: Medical Research Council (MRC) for Transplantation, King's College London, London, United Kingdom.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018920:Coculture Techniques; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000235:genetics; D013234:Stem Cells / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018952:Antigens, CD34; D018932:Chemokine CCL2; D015375:Receptors, Interleukin-2