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 Division of Immunopathology
Department of Pathophysiology and Allergy Research
Center of Pathophysiology, Infectiology & Immunology

Medical University of Vienna

Vienna General Hospital, AKH, 3Q
Waehringer Guertel 18-20
A-1090 Vienna, Austria
 

Rebuilding the 'allergen-specific synaps' with human receptors and allergen relevant for the human disease to investigate mechanisms of antigen-specific immuno-modulation [Pickl]

Project summary 

 T lymphocytes play a central role in the pathogenesis of allergic diseases. During the sensitization phase, priming of allergen-specific CD4+ T helper 2 (TH2) cells results in the production of TH2 cytokines, which are responsible for class switching to the epsilon Ig heavy chain, allowing IgE production by B cells. Once primed, allergen-specific T cells critically contribute to late phase reactions and allergic inflammation in target organs, e.g. in the airways and the skin. In the past, we have explored the usefulness of artificial antigen presenting platforms – based on pseudotyped virus-like particles (VLP) - to modulate allergen-specific T cell responses and we have demonstrated in proof of principle studies that they can drive strong HLA dependent immune responses in vitro and in vivo (1-4). Moreover, we have established a general strategy for the decoration of such antigen-presenting platforms with functionally intact cytokines (2). To better define the T cell side of the ‘allergen-specific synapse’, we have cloned an allergen(Art v 125-36)-specific human T cell receptor (TCR), which we could successfully transfer and functionally express in T cell lines and primary T cells of non-allergic donors (3). Allergen-specific TCR transgenic T cells can be produced in high numbers and shall lay the ground for a better definition of the 'allergen-specific synapse' (5).
Within this project we propose to rebuild the human 'allergen-specific synapse' based on human receptors and antigen relevant for the human disease in an in vivo model. For that purpose we want to generate double-transgenic mice expressing the human Art v 125-36-specific Valpha17/Vbeta18 TCR in concert with HLA-DR1 to study mechanisms of specific immunotherapy in vivo. A special focus will be the comparison between soluble-peptide-induced and antigen-bound-particle-induced immunomodulation. In the latter context, we plan to intensively investigate the potential of our genuine VLP-based antigen presenting platforms both in vitro and in vivo.
Furthermore, we are interested in creating affinity-matured (soluble) versions of the Art v 1-specific TCR for interference with TCR/APC interactions or as targeting agents for immunomodulatory molecules.