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Subproject 1

Human leukocyte antigen (HLA)-transgenic mice as a pre-clinical model of pemphigus vulgaris

Summary

Folie1.PNG

Pemphigus vulgaris (PV) serves as a model disease for an organ-specific, autoantibody-mediated autoimmune disorder. In PV there is a strong genetic association with distinct human leukocyte antigen (HLA) class II alleles. A major aim of this project is to analyse the immune mechanisms that are essential for the development of the disease in an HLA-class II-transgenic mouse model of PV. The role of autoreactive CD4+ T-lymphocytes, that are activated by recognizing defined areas of the major autoantigen demoglein 3(Dsg3), and their function of providing help for the production of Dsg3-specific autoantibodies, that are essential in the pathogenesis of PV, will be investigated and characterized in these mice. Different subtypes of Dsg3-reactive CD4+ T-lymphocytes will be analysed phenotypically and on a functional level. Based on their functional characteristics specific CD4+ T-lymphocyte subtypes will be targeted by applying DNAzyme. A key objective of the project is the induction of a Dsg3-specific T-cell tolerance in this mouse model. The immune mechanisms leading to tolerance induction will be characterized including the identification of regulatory immune cells (regulatory T and B cells) as well as of soluble factors (cytokines). The principal understanding in this pre-clinical model will provide an important basis for the phase Ib trial that investigates the Dsg3-specific tolerance induction in PV patients and the results will lead to an improved understanding of the pathogenesis of this autoimmune disorder.

Applicants:

Prof. Dr. Rüdiger Eming
Universitätsklinikum Gießen und Marburg GmbH
Standort Marburg
Klinik für Dermatologie und Allergologie

Prof. Dr. Holger Garn
Philipps-Universität Marburg
Fachbereich Medizin
Institut für Laboratoriumsmedizin und Pathobiochemie, Molekulare Diagnostik