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Anti-receptor autoantibodies in cardiovascular diseases. Diagnostic and therapeutic implications

Objective

- To define the immunogenic background of` the autoimmune response against G protein coupled cardiovascular receptors.
- To define whether these autoantibodies only reflect all autoimmune status or are responsible for the pathogeny of the disease.
- To define the in vivo effect of functionally active polyclonal and monoclonal
antibodies.

In several cardiovascular diseases (idiopathic dilated cardiomyopathy,
secondary malignant hypertension) the presence has been detected of autoantibodies against cardiovascular receptors belonging to the superfamily of G protein coupled receptors. These autoantibodies have been shown to exert an agonist-like activity on the target receptors in the absence of desensitization. Although the functional properties of these autoantibodies could be of importance in the pathogenesis and/or the development of the diseases in which they are found, there is no direct evidence for this hypothesis.
In order to answer this question, a more thorough characterization of the
cellular and humoral components of the autoimmune response will be performed focusing on the structural recognition at the T cell level (determination of HLA class II molecules related to the presence of these autoantibodies and using peptides derived from the receptors to study their interaction with HLA molecules) and the B cell level (determination of the structure of the B cell epitopes recognized by the functional autoantibodies or by polyclonal and monoclonal antibodies against the target peptides). The receptors studied will be the beta 1- and beta 2-adrenergic receptor, the M2 acetylcholine, the (1-adrenergic, the AT1 angiotensin and the B2 bradykinin receptor.
The polyclonal and monoclonal anti-receptor antibodies will be studied for their pharmacological, biochemical and physiological effects on the target receptors and the cells carrying them (cardiomyocytes).
The animals, immunized with the synthetic peptides and producing functional antibodies, will be studied for histo- and cytopathological changes in the target tissues (heart and vessels). Mice treated with functional monoclonal antibodies will also be studied for similar changes. If the antibodies show to be pathogenic, an experimental animal model will be set up to study the possibility of an immunological therapy (blocking peptides at the B and T cell level).
This project will not only give new insights into cardiovascular diseases
without known origin but also Iead to alternative therapies.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Centre National de la Recherche Scientifique
Address
31,Avenue Monge
37200 Tours
France

Participants (4)

JOHANNES GUTENBERG UNIVERSITAET MAINZ
Germany
Address
6,Duesbergweg 6
55099 Mainz
Onassis Cardiac Surgery Center
Greece
Address
356,Sygrou Avenue
176 74 Kalithea
Stiftung Max-Delbrück-Centrum für Molekulare Medizin
Germany
Address
10,Robert-rössle-straße 10
13125 Berlin
University of Göteborg
Sweden
Address
Sahlgren's Hospital
413 45 Göteborg