HUMAN REGULATORY T CELLS PREVENT ISLET ALLOGRAFT REJECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 25
Author(s):  
Douglas C Wu ◽  
Joanna Wieckiewicz ◽  
Kathryn J Wood
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Islet Transplantation ◽  
Pancreatic Islet ◽  
Allograft Rejection ◽  
Ex Vivo ◽  
Human Islets ◽  
Human Islet ◽  
Pancreatic Islet Transplantation ◽  
Islet Allograft

Background: Type 1 diabetes mellitus represents a significant burden on global healthcare. Pancreatic islet transplantation offers an effective means of controlling the disease, but shortage of donor tissue, graft thrombosis, and immunological rejection after transplantation remain obstacles that need to be overcome. Our aim was to assess the ability of ex vivo expanded human regulatory T cells (Treg) in modulating the rejection response against a human islet allograft in a clinically relevant model of human pancreatic islet transplantation. Methods: We studied the rejection response against allogeneic human islets in acohort of 32 immunodeficient mice which had been reconstituted with a functional human immune system. Thirteen subjects were transplanted with human islets without further immunological modification; graft survival was compared with that of thirteen subjects treated additionally with human regulatory T cells. Six controls were given a human islet transplant, but not reconstituted with human immune cells to demonstrate the functionality of the islet graft in the absence of immunological rejection. Graft function was assessed with serial blood glucose measurements, immunohistochemistry,immunoflourescence, and flow cytometry. Findings: Human islet allografts were rapidly rejected in subjects that did notreceive Treg. With Treg treatment, however, human islet allograft rejection was prevented (median survival time (MST) of > 45 days with Treg, as opposed to an MST of 23 days without Treg). Ex vivo expanded Treg homed to the lymphoid tissue draining the graft site where they suppressed the priming, activation, proliferation, and effector cytokine production of alloreactive T cells. Interpretation: These findings in a clinically relevant model of human pancreatic islet transplantation demonstrate the ability of ex vivo expanded human Treg to attenuate acute islet allograft rejection, and provide further support for their use in cellular immunotherapy.

Cyclosporine Does not Inhibit the Process of Revascularization of Pancreatic Islet Transplantation

1997 ◽  
Vol 6 (1) ◽  
pp. 69-76 ◽  
Author(s):  
José F. Mendola ◽  
Cristian Goity ◽  
Enric Esmatjes ◽  
Alex Saenz ◽  
Laureano Fernandez-Cruz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Islet Transplantation ◽  
Pancreatic Islet ◽  
Allograft Rejection ◽  
Immunosuppressive Drug ◽  
Immunofluorescence Technique ◽  
Pancreatic Islet Transplantation ◽  
Islet Allograft ◽  
Indirect Immunofluorescence Technique ◽  
Liver And Kidney

The immunosuppressive drug cyclosporin-A (CsA) has been widely used to prevent pancreatic islet allograft rejection. Because it has been suggested that CsA may inhibit the process of revascularization of transplanted islets, the purpose of the study was to analyze by a double indirect immunofluorescence technique the revascularization process of isolated islets grafted in the liver and in the renal subcapsular space of rats treated with immunosuppressive doses of CsA. Lewis rats were grafted with either Lewis (isografts) or Wistar (allografts) pancreatic islets obtained by collagenase digestion. Rats were killed at different days after implantation and the liver and kidney bearing the grafted islets were snap frozen and immunohistochemically stained with a double immunofluorescence technique using a rabbit antifactor-VIII antiserum (which labels endothelial cells) and a guinea pig antiinsulin antibody. Islets implanted into nonimmunosuppressed hosts completed revascularization by days 3-7 after transplantation, as shown by the detection of endothelial cells within and surrounding the islets. The identical staining pattern of revascularization was observed in nonrejecting allografts as well as in isografts treated with CsA. We conclude that CsA did not inhibit the process of revascularization of rat islets after free transplantation. This finding is relevant for human islet transplantation, where CsA is currently employed to prevent kidney and islet allograft rejection. Copyright © 1997 Elsevier Science Inc.

scholarly journals Low Dose IL-2 Combined with Rapamycin Led to an Expansion of CD4+CD25+FOXP3+ Tregs and Prolonged Human Islet-allograft Survival in Humanized Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Min Hu ◽  
Wayne J Hawthorne ◽  
Leigh Nicholson ◽  
Heather Burns ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Survival ◽  
Islet Transplantation ◽  
Allograft Rejection ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Human Islet ◽  
Allograft Survival ◽  
Islet Allograft

<a>Islet transplantation is an emerging therapy for type 1 diabetes (T1D) and hypoglycaemic unawareness. However, a key challenge for islet transplantation is cellular rejection and the requirement for long-term immunosuppression. In this study we established a diabetic-humanizedNOD-scidIL2Rnull(NSG) mouse model of T cell mediated human islet-allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin2(IL-2) combined with low-dose rapamycin to prolong graft survival. NSG-mice that had received renal-subcapsular human islet-allografts and were transfused with 1×107 of human-spleen-mononuclear-cells (hSPMCs), reconstituted human CD45+ cells that were predominantly CD3+ T cells and rejected their grafts with a median survival time of 27 days. IL-2 alone (0.3×106 IU/m2 or 1×106 IU/m2), or rapamycin alone (0.5-1mg/kg) for 3 weeks did not prolong survival. However, the combination of rapamycin with IL-2 for 3 weeks significantly prolonged human islet-allograft survival. Graft survival was associated with expansion of CD4+CD25+FOXP3+ Tregs and enhanced TGF-β production by CD4+ T cells. CD8+ T cells showed reduced IFN-γ production and reduced expression of perforin-1. The combination of IL-2 and rapamycin has the potential to inhibit human islet-allograft rejection by expanding CD4+FOXP3+ Tregs in vivo and supressing effector cell function, and could be the basis of effective tolerance-based regimens.</a>

scholarly journals Low Dose IL-2 Combined with Rapamycin Led to an Expansion of CD4+CD25+FOXP3+ Tregs and Prolonged Human Islet-allograft Survival in Humanized Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Min Hu ◽  
Wayne J Hawthorne ◽  
Leigh Nicholson ◽  
Heather Burns ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Survival ◽  
Islet Transplantation ◽  
Allograft Rejection ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Human Islet ◽  
Allograft Survival ◽  
Islet Allograft

<a>Islet transplantation is an emerging therapy for type 1 diabetes (T1D) and hypoglycaemic unawareness. However, a key challenge for islet transplantation is cellular rejection and the requirement for long-term immunosuppression. In this study we established a diabetic-humanizedNOD-scidIL2Rnull(NSG) mouse model of T cell mediated human islet-allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin2(IL-2) combined with low-dose rapamycin to prolong graft survival. NSG-mice that had received renal-subcapsular human islet-allografts and were transfused with 1×107 of human-spleen-mononuclear-cells (hSPMCs), reconstituted human CD45+ cells that were predominantly CD3+ T cells and rejected their grafts with a median survival time of 27 days. IL-2 alone (0.3×106 IU/m2 or 1×106 IU/m2), or rapamycin alone (0.5-1mg/kg) for 3 weeks did not prolong survival. However, the combination of rapamycin with IL-2 for 3 weeks significantly prolonged human islet-allograft survival. Graft survival was associated with expansion of CD4+CD25+FOXP3+ Tregs and enhanced TGF-β production by CD4+ T cells. CD8+ T cells showed reduced IFN-γ production and reduced expression of perforin-1. The combination of IL-2 and rapamycin has the potential to inhibit human islet-allograft rejection by expanding CD4+FOXP3+ Tregs in vivo and supressing effector cell function, and could be the basis of effective tolerance-based regimens.</a>

scholarly journals Ex Vivo Expanded Human Regulatory T Cells Can Prolong Survival of a Human Islet Allograft in a Humanized Mouse Model

2013 ◽  
Vol 96 (8) ◽  
pp. 707-716 ◽  
Author(s):  
Douglas C. Wu ◽  
Joanna Hester ◽  
Satish N. Nadig ◽  
Wei Zhang ◽  
Piotr Trzonkowski ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Mouse Model ◽  
Ex Vivo ◽  
Human Islet ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Islet Allograft

scholarly journals Autologous Regulatory T Cells in Clinical Intraportal Allogenic Pancreatic Islet Transplantation

2021 ◽  
Author(s):  
Marcus Bergström ◽  
Ming Yao ◽  
Malin Müller ◽  
Olle Korsgren ◽  
Bengt von Zur‐Mühlen ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Islet Transplantation ◽  
Pancreatic Islet ◽  
Pancreatic Islet Transplantation
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