Abstracts (complete list) - Wissenschaft Online

Reinhard Maier, Rita De Giuli, Veronika Nindl, Simone Miller, Volker Thiel, Roland
Züst, Ari Waisman, Birgit Ledermann, Burkhard Ludewig
Preventing autoimmune myocarditis through cardiac myosinspecific
tolerance
Virus-induced myocarditis might broaden the pathogen-specific immune response
towards heart antigens such as the abundantly expressed myosin heavy chain alpha
(myhca). The chronic immune response against cardiac self-antigens may lead to
dilative cardiomyopathy (DCM), which represents a prevalent cause of human heart
disease and heart failure. Immunization of BALB/c mice with the myhca-derived peptide
(amino acids 614-629) elicits myocarditis induced by peptide-specific CD4 T cell
responses, and therefore uncouples the chronic autoimmune phase from putative viral
infections. In order to further characterize the mechanisms and effector molecules
involved in autoimmune myocarditis and to evaluate therapeutic strategies, we have
generated a novel transgenic mouse model. In this model (Rosa-IM mouse), the
expression of the myhca peptide is directed to the MHC class II pathway through a
chimeric invariant chain (Ii-myhca) in which the CLIP peptide sequence is replaced by
the myhca614-629 peptide. The construct is designed in such a way that the expression
is only achieved in the presence of Cre-recombinase. The ubiquitous expression of
myhca in all MHC class II positive cells induced specific immune tolerance and as a
consequence mice were protected from myocarditis. The Rosa-IM mouse represents
therefore a versatile tool to dissect the basic mechanisms in autoimmune myocarditis,
to delineate the decision making process between activation and tolerization of heartspecific
CD4 T cells and to study the participation of different antigen presenting cells
like dendritic cells, B cells and macrophages in the disease process.