Effects of CD39 on pancreatic inflammation and fibrosis

• Applicant: Professor Dr. Helmut Friess, since 4/2010
• Subject Area: General and Visceral Surgery
• Term: from 2008 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 71165692

Chronic pancreatitis (CP) is an important and common disease. Clinically, patients with CP present with severe pain, exocrine/endocrine insufficiency, sequelae of inflammation and associated coagulation disturbances. The pathological characteristics are those of inflammatory infiltrates, progressive organ atrophy and fibrosis.CD39, an ectonucleotidase that regulates the conversion of extracellular nucleotides to nucleosides, is expressed on vascular endothelium, T cells and pancreatic stellate cells (PSC). The latter are considered key cells in pancreatic fibrogenesis. Elevated levels of tissue CD39 expression are found in CP and pancreatic cancer human biopsies. We also noted that deletion of CD39 in mutant mice results in decreased pancreatic fibrosis and substantially less atrophy in a model of experimental pancreatitis.Specific cellular immunological effects on the development of fibrosis in CP remain largely unknown. Of special interest in this regard are regulatory T cells (Treg). These cells are important in controlling inflammatory processes and in providing immune tolerance. Our published data indicate that CD39 is a phenotypic marker of Treg and that adenosine generation is responsible for the suppressive properties of these cells. Altered Treg cell function in CD39-null mice is associated with Th1 phenotypic deviation, associated with excessive production of the anti-fibrotic cytokine IFN-γ.In this proposal, we will study the immunomodulatory capacity of CD39 on manifestations of pancreatic inflammation. This will be done by adoptive transfer experiments involving the transfer of CD39-null and wild type bone marrow derived cells and enriched Treg into irradiated and RAG-1 deficient mice in vivo. We will also study the influence of CD39 expression by PSC alone on matrix production and how these PSC interact with Treg to modulate progression of pancreatic inflammation and fibrosis.Our data will provide novel insights into mechanisms of pancreatic injury and fibrogenesis and might indicate future therapeutic avenues in human disease.“

• DFG Programme: Research Grants
• International Connection: USA
• Participating Person: Professor Simon Christopher Robson, Ph.D.
• Ehemaliger Antragsteller: Dr. Beat Martin Künzli, until 4/2010