In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice

Midhat H Abdulreda, R. Damaris Molano, Gaetano Faleo, Maite Lopez-Cabezas, Alexander Shishido, Ulisse Ulissi, Carmen Fotino, Luis F. Hernandez, Ashley Tschiggfrie, Virginia R. Aldrich, Alejandro Tamayo-Garcia, Allison L Bayer, Camillo Ricordi, Diego A Caicedo-Vierkant, Peter Buchwald, Antonello Pileggi, Per Olof Berggren

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalDiabetologia
DOIs
StatePublished - Jan 1 2019

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Inbred NOD Mouse
Type 1 Diabetes Mellitus
Anterior Chamber
Islets of Langerhans
Autoimmunity
Longitudinal Studies
Hyperglycemia
Disease Progression
Pancreas
Fluorescence
Insulin
Inflammation
T-Lymphocytes
Transplants
Kidney

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice. / Abdulreda, Midhat H; Molano, R. Damaris; Faleo, Gaetano; Lopez-Cabezas, Maite; Shishido, Alexander; Ulissi, Ulisse; Fotino, Carmen; Hernandez, Luis F.; Tschiggfrie, Ashley; Aldrich, Virginia R.; Tamayo-Garcia, Alejandro; Bayer, Allison L; Ricordi, Camillo; Caicedo-Vierkant, Diego A; Buchwald, Peter; Pileggi, Antonello; Berggren, Per Olof.

In: Diabetologia, 01.01.2019.

Research output: Contribution to journalArticle

Abdulreda, MH, Molano, RD, Faleo, G, Lopez-Cabezas, M, Shishido, A, Ulissi, U, Fotino, C, Hernandez, LF, Tschiggfrie, A, Aldrich, VR, Tamayo-Garcia, A, Bayer, AL, Ricordi, C, Caicedo-Vierkant, DA, Buchwald, P, Pileggi, A & Berggren, PO 2019, 'In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice', Diabetologia. https://doi.org/10.1007/s00125-019-4879-0
Abdulreda, Midhat H ; Molano, R. Damaris ; Faleo, Gaetano ; Lopez-Cabezas, Maite ; Shishido, Alexander ; Ulissi, Ulisse ; Fotino, Carmen ; Hernandez, Luis F. ; Tschiggfrie, Ashley ; Aldrich, Virginia R. ; Tamayo-Garcia, Alejandro ; Bayer, Allison L ; Ricordi, Camillo ; Caicedo-Vierkant, Diego A ; Buchwald, Peter ; Pileggi, Antonello ; Berggren, Per Olof. / In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice. In: Diabetologia. 2019.
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AU - Molano, R. Damaris

AU - Faleo, Gaetano

AU - Lopez-Cabezas, Maite

AU - Shishido, Alexander

AU - Ulissi, Ulisse

AU - Fotino, Carmen

AU - Hernandez, Luis F.

AU - Tschiggfrie, Ashley

AU - Aldrich, Virginia R.

AU - Tamayo-Garcia, Alejandro

AU - Bayer, Allison L

AU - Ricordi, Camillo

AU - Caicedo-Vierkant, Diego A

AU - Buchwald, Peter

AU - Pileggi, Antonello

AU - Berggren, Per Olof

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N2 - 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.

AB - 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.

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KW - Islet swelling

KW - Local intervention

KW - NOD mice

KW - Non-invasive longitudinal intravital imaging

KW - Pancreatic islet transplant

KW - Prediction of type 1 diabetes

KW - Predictive mathematical model

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