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Pathogenesis of insulin-dependent diabetes mellitus (IDDM with special reference to the mechanisms of enterovirus infection-induced beta cell damage

Objective

Objectives:
The main objective of this research project is to obtain new information on the mechanisms by which enterovirus infections could cause damage to the insulin-producing islet Beta-cells in the pancreas, and facilitate the Beta-cell-destructing autoimmune reactions that eventually lead to onset of clinical juvenile-type (insulin-dependent) diabetes mellitus (IDDM).

The main objective of this research project is to obtain new information on the mechanisms by which enterovirus infections could cause damage to the insulin-producing islet beta cells in the pancreas, and facilitate the beta-cell-destructing autoimmune reactions that eventually lead to onset of clinical juvenile-type (insulin-dependent) diabetes mellitus (IDDM). Systematic evaluation of these potential mechanisms in necessary in order to establish the suggested role of enterovirus infections in the aetiology of IDDM and to be able, in future, to assess possible benefits and risks of putative enterovirus vaccines in prevention of the disease. Several lines of evidence suggest that enterovirus infections may have a role in the etiology of IDDM, which is a major public health problem worldwide. Several possibilities can be envisaged for putative mechanisms of enterovirus infection-induced beta cell damage resulting in impaired insulin production.

Alternative hypotheses implicate:
i) direct virus- induced beta cell death or disturbance (CPE);
ii) virus infection-induced exposure of hidden self-antigens to the immune system;
iii) molecular mimicry initiated by a systemic infection;
iv) non-specific inflammatory "bystander" damage due tolytic or proinflammatory infection of non-beta islet cells or exocrine pancreas or;
v) various combinations of these four.

This collaborative network of research groups combines expertise of different fields and enables multidisciplinary analysis of possible mechanisms of entero virus infection-induced beta cell damage. Together, we have long experience in both clinical and molecular virology, cellular and molecular biology of beta cells in culture, molecular pathogenesis of acute and chronic entero virus infections, studies on entero virus-beta-cell interactions in cell culture, and in diabetes-related human immunology. We work in well-equipped laboratories with access to both conventional and advanced technology, as well as to exceptional research material including cultured human beta cells and blood specimens from both prediabetic human individuals and recent onset IDDM patients. We will also use established animal models of IDDM and plan to construct transgenic animals aimed to be new models of the disease.

Specific tasks in our research are the following:
1. Patterns and consequences of enterovirus replication in cultured beta cells;
2. Enterovirus epitopes inducing cross-reactive autoimmune responses;
3. Transgenic mice expressing enterovirus genes in islet beta cells;
4. Natural course and intervention of development on diabetes in established mouse models.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

National Public Health Institute
Address
166,Mannerheimintie
00300 Helsinki
Finland

Participants (3)

Eberhard-Karls-Universität Tübingen
Germany
Address
8,Liebermeierstraße
72076 Tübingen
UPPSALA UNIVERSITY
Sweden
Address
3,Husargatan 3
751 23 Uppsala
University of Helsinki
Finland
Address
3,Haartmaninkatu
00290 Helsinki