Rational development of treatments for immune mediated diseases is optimally based on detailed understanding of the pathogenesis, especially immunological events in affected organs or tissues. In type 1 (as well as type 2) diabetes, this has been hampered so far by access to and availability of pancreata from patients. However, the recently established repository of pancreatic organ donors ('nPOD') has drastically changed this situation and offers a crucial opportunity to deepen our insight into the human condition - this will not only close gaps, but will (and already has) shift paradigms and enable us to design immune-based interventions in a more targeted fashion. Therefore here, we wish to assess, which cytokines are expressed in human pancreata of patients with type 1 and type 2 diabetes. We will use a combination of strategies to ascertain reliable results including direct in situ immunohistology, in situ hybridization, quantitative PCR as well as laser microdissection. These studies should identify the major cytokines expressed during pathogenesis of human type 1 and type 2 diabetes, the cells which express them and whether their expression is constitutive or linked to a certain stage of the disease or, more likely, stage of local islet destruction. The strategy of directly identifying pivotal immunopathological factors as future therapeutic targets i the affected organ has precedent, as this has been the case for rheumatoid arthritis, where TNF blockers were developed based on Marc Feldman's initial observation of heightened TNF levels in synovial cells from affected joints in rheumatoid arthritis. From a translational angle, we envision that cytokine blockade could be integrated in a combination therapy aimed at long term tolerance induction, ideally complementing immunization regimens that induce regulatory T cells.
Research outlined in this application aims to provide a detailed characterization of the mixture of soluble inflammatory factors ('cytokines'and 'chemokines') in pancreatic islets from diabetes patients. It is anticipated that a better understanding of the local tissue environment in a unique set of optimally preserved samples will enable a more rational approach toward therapeutic blockade of these factors. Our approach is modeled after the identification of TNF as a crucial cytokine in rheumatoid arthritis, which has led to the introduction of a highly effective class of anti-TNF drugs.
|Van Belle, Tom L; Pagni, Philippe P; Liao, Jeanette et al. (2014) Beta-cell specific production of IL6 in conjunction with a mainly intracellular but not mainly surface viral protein causes diabetes. J Autoimmun 55:24-32|