MECHANISMS OF ESTABLISHMENT AND MAINTENANCE OF IMMUNOLOGICAL TOLERANCE
SFB-F23 A SPEZIALFORSCHUNGSBEREICH FUNDED BY THE FWF
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MECHANISMS OF ESTABLISHMENT AND MAINTENANCE OF IMMUNOLOGICAL TOLERANCESFB-F23 A SPEZIALFORSCHUNGSBEREICH FUNDED BY THE FWF |
MEMBERS Wilfried Ellmeier |
Josef Penninger
Institute of Molecular Biotechnology (IMBA)
Dr.Bohrgasse 3-5
1030 Wien
AUSTRIA
Tel.: +43-1-79730-454
Fax: +43-1-79730-459
josef.penninger@imba.oeaw.ac.at
http://www.imba.oeaw.ac.at/
SFB co-workers:
We have recently established the first model that makes it possible to trigger an autoimmune heart disease in naïve, non-transgenic mice using dendritic cells loaded with heart specific self-peptides . It has been estimated that as many as 50% of patients with chronic heart failure and cardiomyopathies develop disease following inflammation. A single injection of as few as 50-100,000 DCs into completely naïve Balb/c mice induces massive, CD4 + T cell mediated heart inflammation followed by post-inflammatory heart failure. Mechanistically, Toll-like receptor (TLR) stimulation in concert with CD40 activation of self peptide-loaded DCs are essential for disease induction. After resolution of acute myocarditis, mice developed heart failure; moreover, TLR-stimulation in these mice resulted in relapse of inflammatory infiltrates. Importantly, injection of damaged, syngeneic cardiomyocytes also induced myocarditis in mice if TLRs were activated in vivo. Thus, the concerted action of innate and adaptive immunity on dendritic cells triggers autoimmune heart disease and heart failure following resolution of the heart inflammation. These results provide a unifying theory as to how tissue damage and multiple infectious triggers can induce autoimmune diseases, relapses, and chronic cardiomyopathy This system also allows us to genetically dissect signaling pathways in DCs that determine whether DCs induce tolerance or induce autoimmunity using an in vivo model system.
Our SFB experiments are designed to expand on these findings and to identify genes and the molecular mechanisms that are critical in DC biology, DC-mediated immunotolerance, and/or DC-mediated autoimmune diseases.