Project Details
Projekt
Generation and characterization of an antibody-based mouse model for systemic sclerosis
Subject Area
Rheumatology
Term
from 2015 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 272606465
In the previous period, we have generated a novel mouse model induced by autoimmunity against the human angiotensin receptor type-1 (AT1R) resembling several features of systemic sclerosis (SSc), e.g. fibrosis, vasculopathy, and autoimmunity. The clinical phenotype of these mice is very similar to the phenotype of mice induced by immunization against the human endothelin receptor type-A (ETAR) analyzed in parallel. Disease can be transferred into C56/Bl6 mice by adoptive transfer of splenocytes. Functional activity of antibodies (ab) from hAT1R-immunized mice was shown by their ability to induce IL-8 and to increase the spontaneous beating rate in rat cardiomyocytes. In the applied period, we aim to further characterize the hAT1R-immunized mouse model. We want to identify the dynamic of the disease process and the role of receptor expression on immune cell function, for immune cell homeostasis, and on tissues for local Infiltration. Anti-AT1R ab will be phenotypically and functionally characterized by studying their specificity, their recognized epitopes, their glycosylation, their affinity, and their differences to anti-ETAR ab. We aim to study in vitro the effects of the anti-AT1R ab on cytokine induction, cell signaling, and mRNA transcription particularly for the generation of IL-6 and TGFß, which are key cytokines in SSc. In vivo, we will identify the effects of the antibodies to induce SSc features. To proof the causal role ab-induced AT1R activation, we will apply AT1R-deficient mice and will use Fab fragments of IgG from AT1R-immunized mice as well as from monoclonal functional anti-AT1R antibodies. AT1R immunization of FcɣR-deficient mice will clarify the role of the constant ab region to induce pathologies. By using adoptive transfer experiments, we will further identify immune cells causing or contributing to the disease phenotype. We hope to identify novel disease mechanisms and therapeutic targets.
DFG Programme
Research Grants
