Lars Krogvold1,2, Anna Wiberg3, Bjørn Edwin4,5, Trond Buanes4,6, Frode Lars Jahnsen7,8, Kristian F Hanssen4,9, Erik Larsson3, Olle Korsgren3, Oskar Skog3, Knut Dahl-Jørgensen10,4. 1. Paediatric Department, Oslo University Hospital HF, PO Box 4950, Nydalen, N-0424, Oslo, Norway. lars.krogvold@gmail.com. 2. Faculty of Medicine, University of Oslo, Oslo, Norway. lars.krogvold@gmail.com. 3. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 4. Faculty of Medicine, University of Oslo, Oslo, Norway. 5. The Intervention Centre, Oslo University Hospital, Oslo, Norway. 6. Department of Surgery, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway. 7. Department of Pathology, Oslo University Hospital, Oslo, Norway. 8. Centre for Immune Regulation, University of Oslo, Oslo, Norway. 9. Department of Endocrinology, Oslo University Hospital, Oslo, Norway. 10. Paediatric Department, Oslo University Hospital HF, PO Box 4950, Nydalen, N-0424, Oslo, Norway.
Abstract
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.
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.
Entities:
Keywords:
Gene expression; Inflammation; Insulin; Insulitis; Pancreas; T cells; Type 1 diabetes
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