- Project description
The aim of the subproject is a mechanistic understanding of the anti-inflammatory action of Atrosab to support and complement the parallel clinical phase I study, which exploits the utility of selective TNFR1 targeting as an alternative to global inhibition of TNF. In addition to an apparent direct beneficial effect on systemic inflammation through blockade of TNFR signaling of cells of the innate immune system, we will focus on the adaptive immune response and the T-cell compartment, because here differences between global TNF blockers and receptor-selective interventions are to be expected. By these studies we will gain deeper knowledge about the cellular target of Atrosab in the T-cell compartment and its immunoregulatory potential with respect to modulation of T-cell activation and its potential impact on the regulatory T-cell system. Analyses of peripheral blood T cells from untreated, healthy donors as well as from participants of the phase 1 clinical trial before and after Atrosab treatment will reveal immediate impacts on the T-cell system with respect to subset distribution and functional activities. Further, through analyses of a specific transgenic mouse model, a huTNFR1 k/i line, we will learn about the in vivo efficacy of Atrosab in models of chronic inflammatory diseases such as collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). These data will have direct implications for a potential therapeutic effect of Atrosab.
- Universität Stuttgart, Center Systems Biology (CSB), Stuttgart: K. Pfizenmaier (Coordinator)
- Universität Stuttgart, IZI, Stuttgart: K. Pfizenmaier, R. Kontermann
- Celonic GmbH, Jülich: A. Herrmann