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Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Korsgren)
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 3, 492-501 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

It is thought that T cells play a major role in the immune-mediated destruction of beta cells in type 1 diabetes, causing inflammation of the islets of Langerhans (insulitis). The significance of insulitis at the onset of type 1 diabetes is debated, and the role of the T cells poorly understood.

Methods

In the Diabetes Virus Detection (DiViD) study, pancreatic tissue from six living patients with recent-onset type 1 diabetes was collected. The insulitis was characterised quantitatively by counting CD3+ T cells, and qualitatively by transcriptome analysis targeting 84 T and B lymphocyte genes of laser-captured microdissected islets. The findings were compared with gene expression in T cells collected from kidney biopsies from allografts with ongoing cellular rejection. Cytokine and chemokine release from isolated islets was characterised and compared with that from islets from non-diabetic organ donors.

Results

All six patients fulfilled the criteria for insulitis (5–58% of the insulin-containing islets in the six patients had ≥ 15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61–83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet-infiltrating T cells showed only background levels of cytokine/chemokine release in vitro.

Conclusions/interpretation

Insulitis and a significant reserve reservoir for insulin production were present in all six cases of recent-onset type 1 diabetes. Furthermore, the expression patterns and levels of cytokines argue for a different role of the T cells in type 1 diabetes when compared with allograft rejection.

Place, publisher, year, edition, pages
2016. Vol. 59, no 3, 492-501 p.
Keyword [en]
Gene expression; Inflammation; Insulin; Insulitis; Pancreas; T cells; Type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-274977DOI: 10.1007/s00125-015-3820-4ISI: 000377302900012PubMedID: 26602422OAI: oai:DiVA.org:uu-274977DiVA: diva2:898049
Funder
Novo NordiskSwedish Child Diabetes FoundationSwedish Diabetes Association
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2016-01-27 Created: 2016-01-27 Last updated: 2017-11-30Bibliographically approved
In thesis
1. Immunopathology of the Pancreas in Type 1 Diabetes
Open this publication in new window or tab >>Immunopathology of the Pancreas in Type 1 Diabetes
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) results from a loss of functional insulin-producing pancreatic beta cells. The etiology of T1D is poorly understood, but the detection of infiltrating inflammatory cells in the pancreas and circulating autoantibodies has led to the common notion that an autoimmune process plays a central role in the pathogenesis of the disease.

The aim of this doctoral thesis was to assess various aspects of the immunopathology of type 1 diabetes. To this purpose, studies have been conducted on pancreatic material from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection, the Nordic Network for Islet Transplantation, and the Diabetes Virus Detection (DiViD) study.

Paper I is a study on pancreatic tissue from organ donors with varying duration of T1D as well as non-diabetic donors and subjects with other types of diabetes, in which persistent expression of glucose transporters was shown on the beta cell membrane despite several years of T1D. Glucose transporter 1 was also confirmed as the predominant glucose transporter on human pancreatic islets. In paper II, we report on signs of inflammation in the exocrine but not in the endocrine pancreas in non-diabetic organ donors with diabetes-related autoantibodies, suggesting that diabetes-associated autoantibodies can occur in response to unspecific pancreatic lesions.

Paper III aimed to characterize the T cell-infiltration of pancreatic islets in material from recent-onset T1D patients. Insulitis was shown in all subjects, but with distinct differences in expression analysis of T- and B cell activation to cell-mediated allorejected kidney transplant. Also Paper IV was conducted on material from recent-onset cases and showed increased islet glucagon content, in combination with a reduced number of islets but sustained mean islet size.

Together, these results provide expansion of our knowledge of the immunopathology in T1D, and will hopefully assist in bringing us towards a deeper understanding of T1D aetiology and eventually an effective cure.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1263
Keyword
Type 1 diabetes, glucagon, T cells, autoantibodies, glucose transporters, islets of Langerhans, pancreas
National Category
Endocrinology and Diabetes Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-304621 (URN)978-91-554-9711-8 (ISBN)
Public defence
2016-11-24, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2016-11-01 Created: 2016-10-06 Last updated: 2016-11-02

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Wiberg, AnnaLarsson, ErikKorsgren, OlleSkog, Oskar

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