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Inflammatory mediators expressed in human islets of Langerhans: implications for clinical islet transplantation
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
2003 In: Biochemical and Biophysical Research Communications, ISSN 0006-291, no 308, 474-479 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. no 308, 474-479 p.
Identifiers
URN: urn:nbn:se:uu:diva-96815OAI: oai:DiVA.org:uu-96815DiVA: diva2:171518
Available from: 2008-03-14 Created: 2008-03-14Bibliographically approved
In thesis
1. Inflammatory Mediators and Enterovirus Infections in Human Islets of Langerhans
Open this publication in new window or tab >>Inflammatory Mediators and Enterovirus Infections in Human Islets of Langerhans
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is due to a selective loss of the insulin producing β-cells. However, the process responsible for this loss is still unknown. There is accumulating evidence that enteroviruses (EVs) are involved in T1D. In addition to direct virus-induced cytolysis, EVs could facilitate β-cell destruction by inducing inflammatory cytokines. Induction of such genes has previously been shown in EV-infected islets in vitro. Modulation of inflammatory mediators expressed in the islets could be a possible strategy to reduce β-cell destruction.

In the first paper we screened uninfected isolated human islets for genes with the potential to induce or modulate an immune response. We found that several of the genes expressed in the islets encode proteins with a powerful biological activity, such as IL-1β, IL-8, MIP-2α, MCP-1 and MIF. This indicates that the islets themselves can express several triggers of inflammation, and if expressed in vivo these mediators would probably contribute to β-cell destruction.

The vitamin B3 derivate, nicotinamide (NA), has been shown to modulate expression of factors important for coagulation and inflammatory responses. Addition of NA into isolated islet cultures resulted in a reduced expression of the pro-inflammatory chemokine MCP-1 and the coagulation activator tissue factor, suggesting that NA may have implications for both inflammatory responses and the pro-coagulant activity of islets.

We successfully isolated EVs from three newly diagnosed T1D patients. All isolates showed tropism for human islets and β-cells in vitro and clearly affected islet function. We also found that EV infection induced islet secretion of the chemokines IP-10 and MCP-1and that this induction could be blocked or reduced by addition of NA to the culture medium. Interestingly, NA also reduced viral replication and virus-induced islet destruction.

To conclude, this thesis provides new information about expression and modulation of inflammatory mediators in infected and uninfected human islets that could trigger inflammatory reactions leading to β-cell destruction. Moreover, it further strengthens the causal relationship between EV and T1D.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 316
Keyword
Immunology, diabetes, islets of Langerhans, enterovirus, inflammatory mediators, cytokines, nicotinamide, Immunologi
Identifiers
urn:nbn:se:uu:diva-8501 (URN)978-91-554-7112-5 (ISBN)
Public defence
2008-04-05, Rudbecksalen, Rudbecklaboratoiet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-03-14 Created: 2008-03-14Bibliographically approved
2. Formation of Composite Islet Grafts: A novel strategy to promote islet survival and revascularization
Open this publication in new window or tab >>Formation of Composite Islet Grafts: A novel strategy to promote islet survival and revascularization
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The islets of Langerhans are small and delicate spheroid organs scattered in the pancreas responsible for insulin production. Transplantation of isolated islets is a beneficial therapy for patients with a severe form of type 1 diabetes. The islets, which normally are richly vascularized in the pancreas, are completely disconnected from the vascular support by the enzymatic digestion during the isolation procedure. Islet viability is affected throughout all steps in this process, from donor death and isolation of islets to culturing and the transplantation process itself.

In this thesis a novel strategy to promote islet survival and to re-establish islet vasculature is presented. We show endogenous expression of 51 different genes related to inflammation in cultured islets. Among these genes high expression of MCP-1, MIF, VEGF, thymosin b-10 and IL-8, IL-1β, IL-5R-a, IFN-γ antagonist were found in all donors during the 5- and the 2-day cultures, respectively. Protein expression of these genes can stimulate inflammatory immune responses but also promote tissue repair by attracting curative cells such as endothelial cells (EC) leading to re-establishment of the vasculature.

We have established a novel technique by formation of composite islets using EC and mesenchymal stem cells (MSC). EC adhered on the surface of the islets and created a potential blood tolerant surface. The EC-islets showed a degree of protection from the detrimental effects of instant blood-mediated inflammatory reaction (IBMIR) with the major components of IBMIR being decreased in in vitro assays. We combined MSC to the EC-islets with success. The MSC were found to have proliferative effect on EC and the combination of these two cell types on the islets further increased the EC covered surface compared to EC-islets. The EC-MSC-islets in co-culture formed vessel-like structures both into the islets and out to the surrounding matrix. The MSC enhanced the exogenous EC to form vessel-like network in the EC-MSC-islets indicating vascular support by the MSC.

The novel strategy and conditions presented herein could alleviate problems related to survival of the islets by promoting revascularization. This would open up a new era in islet transplantation and allow more patients to benefit from this therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 463
Series
Keyword
Islet of Langerhans, cytokines and cytokinereceptors expression, endothelial cells, mesenchymal stromal cells, transplantation, revascularization
National Category
Immunology in the medical area
Research subject
cellforskning
Identifiers
urn:nbn:se:uu:diva-102788 (URN)978-91-554-7551-2 (ISBN)
Public defence
2009-06-12, Rudbecksalen, Daghammarskjöldsv. 20, UPPSALA, 09:15 (English)
Opponent
Supervisors
Projects
Clinical immunology, islet group
Available from: 2009-05-20 Created: 2009-05-11 Last updated: 2009-05-20Bibliographically approved

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