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RANTES/CCL5 secretion during enterovirus infection of isolated human pancreatic islets and human islets derived-cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-95031OAI: oai:DiVA.org:uu-95031DiVA: diva2:169087
Available from: 2006-10-31 Created: 2006-10-31 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Studies of the Effect of Enterovirus Infection on Pancreatic Islet Cells
Open this publication in new window or tab >>Studies of the Effect of Enterovirus Infection on Pancreatic Islet Cells
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Enterovirus (EV) infections have been associated with the pathogenesis of Type 1 Diabetes (T1D). However, the pathway(s) by which EV may induce or accelerate diabetes is not well understood. The purpose of this thesis was to obtain new information on the mechanism by which EV infections, with different strains of EV, could cause damage to the insulin-producing β-cells in isolated human islets and in a rat insulin-producing cell line (RINm5F).

Infection with EV strains isolated from T1D patients revealed replication/cell destruction in human islets and EV-like particles in the cytoplasm of the β-cell and infection with the isolates affected the release of insulin in response to glucose stimulation as early as three days post infection, before any decrease in cell viability was observed. A decrease in the induction/secretion of the chemokine RANTES in human islets during EV infection was also detected. When islets were cultured with nicotinamide (NA) the secretion of RANTES was increased irrespectively if the islets were infected or not. In addition, the degree of virus-induced cytolysis of human islets was reduced by NA, suggesting an antiviral effect of NA. Infection with EV strains revealed permissiveness to islet-derived cells.

All EV strains used for infection were able to replicate in the RIN cell clusters (RCC) but not in the RIN cells that were cultured as a monolayer. This might be due to the differences in expression of the Coxsackie-adenovirus receptor (CAR), which only could be detected on the RCC. Infection of RCC with a CBV-4 strain did not affect cell viability and did not induce nitric oxide (NO) production alone or with the addition of IFN-γ. This was in contrast to the results obtained with synthetic dsRNA, poly(IC), which induced NO, suggesting that synthetic dsRNA does not mimic enteroviral intermediate dsRNA.

During analyses performed with the samples from a family where the mother and one son where diagnosed with T1D on the same day, the results showed that the whole family had a proven EV infection at the time diagnosis.

To conclude, the ability of EV strains to replicate in RIN cells is dependent on the growth pattern of the cells and this may be due to the upregulation and/or changed expression pattern of CAR in these cells. In the RIN cells, contrary to artificial dsRNA, viral dsRNA does not induce NO. The isolated EV virus strains used were able to infect and affect human pancreatic islets in vitro. The chemokine RANTES is reduced during an EV infection of human pancreatic islets and NA causes upregulation of RANTES in infected and uninfected islets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 188
Medical sciences, type 1 diabetes, Human pancreatic islets, β-cells, chemokines, enterovirus, MEDICIN OCH VÅRD
urn:nbn:se:uu:diva-7208 (URN)91-554-6692-3 (ISBN)
Public defence
2006-11-21, Rosénsalen, Ing. 95/96, Akademiska Barnsjukhuset SE-751 85, Uppsala, 09:15
Available from: 2006-10-31 Created: 2006-10-31Bibliographically approved

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