Browsing by Author "Fischer, Roman"

Now showing 1 - 4 of 4

Open Access
Co-modulation of TNFR1 and TNFR2 in an animal model of multiple sclerosis
(2023) Fiedler, Timon; Fairless, Richard; Pichi, Kira; Fischer, Roman; Richter, Fabian; Kontermann, Roland E.; Pfizenmaier, Klaus; Diem, Ricarda; Williams, Sarah K.
BackgroundTumour necrosis factor (TNF) is a pleiotropic cytokine and master regulator of the immune system. It acts through two receptors resulting in often opposing biological effects, which may explain the lack of therapeutic potential obtained so far in multiple sclerosis (MS) with non-receptor-specific anti-TNF therapeutics. Under neuroinflammatory conditions, such as MS, TNF receptor-1 (TNFR1) is believed to mediate the pro-inflammatory activities associated with TNF, whereas TNF receptor-2 (TNFR2) may instead induce anti-inflammatory effects as well as promote remyelination and neuroprotection. In this study, we have investigated the therapeutic potential of blocking TNFR1 whilst simultaneously stimulating TNFR2 in a mouse model of MS.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG35-55) in humanized TNFR1 knock-in mice. These were treated with a human-specific TNFR1-selective antagonistic antibody (H398) and a mouse-specific TNFR2 agonist (EHD2-sc-mTNFR2), both in combination and individually. Histopathological analysis of spinal cords was performed to investigate demyelination and inflammatory infiltration, as well as axonal and neuronal degeneration. Retinas were examined for any protective effects on retinal ganglion cell (RGC) degeneration and neuroprotective signalling pathways analysed by Western blotting.ResultsTNFR modulation successfully ameliorated symptoms of EAE and reduced demyelination, inflammatory infiltration and axonal degeneration. Furthermore, the combinatorial approach of blocking TNFR1 and stimulating TNFR2 signalling increased RGC survival and promoted the phosphorylation of Akt and NF-κB, both known to mediate neuroprotection.ConclusionThese results further support the potential of regulating the balance of TNFR signalling, through the co-modulation of TNFR1 and TNFR2 activity, as a novel therapeutic approach in treating inflammatory demyelinating disease.
Open Access
Role of peripheral immune cells for development and recovery of chronic pain
(2021) Bethea, John R.; Fischer, Roman
Chronic neuropathic pain (CNP) is caused by a lesion or disease of the somatosensory nervous system. It affects ~8% of the general population and negatively impacts a person's level of functioning and quality of life. Its resistance to available pain therapies makes CNP a major unmet medical need. Immune cells have been shown to play a role for development, maintenance and recovery of CNP and therefore are attractive targets for novel pain therapies. In particular, in neuropathic mice and humans, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of CNP. Importantly, immunity not only controls pain development and maintenance, but is also essential for pain resolution. In particular, regulatory T cells, a subpopulation of T lymphocytes with immune regulatory function, and macrophages were shown to be important contributors to pain recovery. In this review we summarize the interactions of the peripheral immune system with the nervous system and outline their contribution to the development and recovery of pain.
Open Access
A soluble TNF receptor 2 agonist as a new therapeutic approach to treat autoimmune and demyelinating diseases
(2011) Fischer, Roman; Pfizenmaier, Klaus (Prof. Dr.)
Tumor necrosis factor (TNF) exerts its biological functions via two distinct receptors. Whereas the TNF receptor (TNFR) 1 mainly mediates inflammatory responses, the TNFR2 is involved in tissue protection and regeneration. Accordingly, TNF variants selectively activating TNFR2 could potentially be useful as therapeutic regimen in a variety of diseases. In this study, there was developed a TNFR2-specific agonist, which may be a promising therapeutic in immune- and neurodegenerative diseases. In addition, the molecular mechanisms of TNFR2 signaling and turnover at the membrane were further unrevealed. Endocytosis is an important mechanism to regulate TNF signaling. In contrast to TNFR1, the relevance of receptor internalization for signaling as well as the fate and route of internalized TNFR2 is poorly understood. Upon generation of a human TNFR2-expressing mouse embryonic fibroblast cell line in a TNFR1-/-/TNFR2-/--background, I could demonstrate that TNFR2 was internalized together with its ligand and cytoplasmic binding partners. The internalization was dependent on a di-leucin motif in the cytoplasmic part of TNFR2 and the colocalization of the receptor-complex with clathrin suggested clathrin-mediated internalization of TNFR2. Internalization-defective TNFR2 mutants were capable to signal, i.e. activate NFkB, demonstrating that the di-leucin motif-dependent internalization is dispensable for this response. Therefore receptor internalization primarily seems to serve as a negative feed-back to limit TNF responses via TNFR2. Soluble recombinant TNF is a strong mediator of inflammation, predominantly through TNFR1 activation, as soluble TNF is not sufficient to activate TNFR2. In contrast, the membrane-bound form of TNF (memTNF) fully activates both TNFRs. Therefore, TNFR2-specific therapeutics need to comply with two basic requirements: mimicry of memTNF and, in order to avoid dose limiting severe inflammatory responses, receptor selectivity. As a basis for the construction of a memTNF-mimetic, TNFR2-selective TNF variant, a single-chain TNF (scTNF) molecule was used, that consists of three TNF monomers fused by short peptide linkers. Introducing two amino acid exchanges (D143N/A145R) into a scTNF variant resulted in the loss of TNFR1 affinity under retention of TNFR2 binding. To mimic memTNF, such a receptor-selective single-chain TNF (scTNFR2) was linked to the tenascin C (TNC) trimerization domain, resulting in stabilized TNC-scTNFR2 nonamers with respect to the TNF domains. In vitro TNC-scTNFR2 demonstrated memTNF-mimetic activity and exclusively activated TNFR2. TNC-scTNFR2-enhanced T cell activation was shown by the increased interleukin 2-dependent interferon gamma production. More revealing, TNC-scTNFR2 increased the number of regulatory FoxP3+/CD25+ T cells in cultures of human peripheral blood mononuclear cells, suggesting a potential role in downregulation of T cell immune responses. In cultures of primary astrocytes TNC-scTNFR2 induced the upregulation of ciliary neurotrophic factor, a neurotrophic factor, which enhances the formation of myelin. In addition, in in vitro cultures, TNC-scTNFR2 rescued differentiated neurons from hydrogen peroxide-induced cell death. First in vivo studies on the pharmacokinetic behavior and potential systemic responses in huTNFR2-transgenic mice revealed that compared to TNF, TNC-scTNFR2 has a dramatically extended plasma half-life, yet shows no signs of systemic toxicity and thus is well tolerated even at doses several fold above the MTD of wildtype TNF. These results warrant further studies on the therapeutic usefulness of TNC-scTNFR2 in appropriate animal models of autoimmune and neurodegenerative diseases.
Open Access
The TNFR1 antagonist Atrosimab is therapeutic in mouse models of acute and chronic inflammation
(2021) Richter, Fabian; Williams, Sarah K.; John, Katharina; Huber, Carina; Vaslin, Camille; Zanker, Henri; Fairless, Richard; Pichi, Kira; Marhenke, Silke; Vogel, Arndt; Dhaen, Marie-Ann; Herrmann, Stefanie; Herrmann, Andreas; Pfizenmaier, Klaus; Bantel, Heike; Diem, Ricarda; Kontermann, Roland E.; Fischer, Roman
Therapeutics that block tumor necrosis factor (TNF), and thus activation of TNF receptor 1 (TNFR1) and TNFR2, are clinically used to treat inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, TNFR1 and TNFR2 work antithetically to balance immune responses involved in inflammatory diseases. In particular, TNFR1 promotes inflammation and tissue degeneration, whereas TNFR2 contributes to immune modulation and tissue regeneration. We, therefore, have developed the monovalent antagonistic anti-TNFR1 antibody derivative Atrosimab to selectively block TNFR1 signaling, while leaving TNFR2 signaling unaffected. Here, we describe that Atrosimab is highly stable at different storage temperatures and demonstrate its therapeutic efficacy in mouse models of acute and chronic inflammation, including experimental arthritis, non-alcoholic steatohepatitis (NASH) and experimental autoimmune encephalomyelitis (EAE). Our data support the hypothesis that it is sufficient to block TNFR1 signaling, while leaving immune modulatory and regenerative responses via TNFR2 intact, to induce therapeutic effects. Collectively, we demonstrate the therapeutic potential of the human TNFR1 antagonist Atrosimab for treatment of chronic inflammatory diseases.