Midhat H Abdulreda1,2,3,4, R Damaris Molano5, Gaetano Faleo5, Maite Lopez-Cabezas5, Alexander Shishido5, Ulisse Ulissi5, Carmen Fotino5, Luis F Hernandez5, Ashley Tschiggfrie5, Virginia R Aldrich5, Alejandro Tamayo-Garcia5,6, Allison S Bayer5,7, Camillo Ricordi5,8,7,9,10, Alejandro Caicedo6, Peter Buchwald11,12, Antonello Pileggi13,14,15,16,17, Per-Olof Berggren18,19,20,21. 1. Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA. mabdulreda@miami.edu. 2. Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. mabdulreda@miami.edu. 3. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA. mabdulreda@miami.edu. 4. Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA. mabdulreda@miami.edu. 5. Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA. 6. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. 7. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA. 8. Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. 9. Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA. 10. Diabetes Research Institute Federation, Hollywood, FL, USA. 11. Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA. pbuchwald@miami.edu. 12. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. pbuchwald@miami.edu. 13. Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA. antonello.pileggi@nih.gov. 14. Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. antonello.pileggi@nih.gov. 15. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA. antonello.pileggi@nih.gov. 16. Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA. antonello.pileggi@nih.gov. 17. Center for Scientific Review, National Institutes of Health, 6701 Rockledge Drive, Bethesda, MD, 20892, USA. antonello.pileggi@nih.gov. 18. Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA. per-olof.berggren@ki.se. 19. Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. per-olof.berggren@ki.se. 20. Diabetes Research Institute Federation, Hollywood, FL, USA. per-olof.berggren@ki.se. 21. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-17176, Stockholm, Sweden. per-olof.berggren@ki.se.
Abstract
AIMS/HYPOTHESIS: Autoimmune attack against the insulin-producing beta cells in the pancreatic islets results in type 1 diabetes. However, despite considerable research, details of the type 1 diabetes immunopathology in situ are not fully understood mainly because of difficult access to the pancreatic islets in vivo. METHODS: Here, we used direct non-invasive confocal imaging of islets transplanted in the anterior chamber of the eye (ACE) to investigate the anti-islet autoimmunity in NOD mice before, during and after diabetes onset. ACE-transplanted islets allowed longitudinal studies of the autoimmune attack against islets and revealed the infiltration kinetics and in situ motility dynamics of fluorescence-labelled autoreactive T cells during diabetes development. Ex vivo immunostaining was also used to compare immune cell infiltrations into islet grafts in the eye and kidney as well as in pancreatic islets of the same diabetic NOD mice. RESULTS: We found similar immune infiltration in native pancreatic and ACE-transplanted islets, which established the ACE-transplanted islets as reliable reporters of the autoimmune response. Longitudinal studies in ACE-transplanted islets identified in vivo hallmarks of islet inflammation that concurred with early immune infiltration of the islets and preceded their collapse and hyperglycaemia onset. A model incorporating data on ACE-transplanted islet degranulation and swelling allowed early prediction of the autoimmune attack in the pancreas and prompted treatments to intercept type 1 diabetes. CONCLUSIONS/ INTERPRETATION: The current findings highlight the value of ACE-transplanted islets in studying early type 1 diabetes pathogenesis in vivo and underscore the need for timely intervention to halt disease progression.
AIMS/HYPOTHESIS: Autoimmune attack against the insulin-producing beta cells in the pancreatic islets results in type 1 diabetes. However, despite considerable research, details of the type 1 diabetes immunopathology in situ are not fully understood mainly because of difficult access to the pancreatic islets in vivo. METHODS: Here, we used direct non-invasive confocal imaging of islets transplanted in the anterior chamber of the eye (ACE) to investigate the anti-islet autoimmunity in NODmice before, during and after diabetes onset. ACE-transplanted islets allowed longitudinal studies of the autoimmune attack against islets and revealed the infiltration kinetics and in situ motility dynamics of fluorescence-labelled autoreactive T cells during diabetes development. Ex vivo immunostaining was also used to compare immune cell infiltrations into islet grafts in the eye and kidney as well as in pancreatic islets of the same diabeticNODmice. RESULTS: We found similar immune infiltration in native pancreatic and ACE-transplanted islets, which established the ACE-transplanted islets as reliable reporters of the autoimmune response. Longitudinal studies in ACE-transplanted islets identified in vivo hallmarks of islet inflammation that concurred with early immune infiltration of the islets and preceded their collapse and hyperglycaemia onset. A model incorporating data on ACE-transplanted islet degranulation and swelling allowed early prediction of the autoimmune attack in the pancreas and prompted treatments to intercept type 1 diabetes. CONCLUSIONS/ INTERPRETATION: The current findings highlight the value of ACE-transplanted islets in studying early type 1 diabetes pathogenesis in vivo and underscore the need for timely intervention to halt disease progression.
Entities:
Keywords:
Anterior chamber of the eye; Autoimmune diabetes; Diabetes recurrence; Diabetes transfer; Immune modulation; Intraocular transplantation; Islet degranulation; Islet inflammation; Islet swelling; Local intervention; NOD mice; Non-invasive longitudinal intravital imaging; Pancreatic islet transplant; Prediction of type 1 diabetes; Predictive mathematical model
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