Special Report: Modulating the immune response

image1Collaboration between the universities of Groningen and Stuttgart has revealed new treatments for neurological disorders 

The tumour necrosis factor (TNF) is a master, pro-inflammatory cytokine that plays an important role in the initiation and orchestration of immunity and inflammation. Elevated TNF levels can lead to chronic inflammation and tissue damage, and have been associated with different autoimmune diseases. Therefore, several anti-TNF therapeutics are clinically approved and successfully used to treat autoimmune diseases such as rheumatoid arthritis. TNF is also known to play an important role in various neurodegenerative diseases, including Alzheimer’s disease and multiple sclerosis (MS). However, anti-TNF therapeutics has failed in MS clinical trials.

Two research groups (one at the Institute of Cell Biology and Immunology of the University of Stuttgart, Germany, led by Professors Klaus Pfizenmaier and Roland Kontermann; and the other at the University of Groningen, the Netherlands, led by Professor Ulrich Eisel) have shown in previous collaborative research with cell and animal models that failure of anti-TNF therapeutics in neurological disorders is most likely due to the antithetic effects of the two TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. In their present work the authors have developed a novel animal model and novel TNFR-selective reagents, i.e. a TNFR1 antagonist and a TNFR2 agonist, to provide in vivo proof of concept that TNFR selective intervention is an effective therapeutic strategy in in vitro and in vivo models of excitotoxic brain damage, related to Alzheimer’s and other neurodegenerative diseases.

Specifically, they show that both a TNFR1 antagonistic antibody and a specifically engineered TNFR2 selective agonistic TNF molecule promote neuronal survival and rescue from damage-induced neurologic deficits, as revealed from histochemical and behavioural studies respectively. Most importantly, neuroprotection mediated by the TNFR1 antagonist is abrogated by a simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signalling and why anti-TNF drugs failed in the treatment of neurodegenerative diseases. The implications of this findingare far-reaching.

To achieve this in vivo proof of therapeutic activity of the novel molecules, it was necessary to develop an animal model suitable to respond to these human reagents, which are specific for human TNF receptors. This was successfully accomplished by generating mouse lines in which parts of the two mouse TNFR genes were exchanged for the respective parts of the two human TNFR genes. The approach was possible due to the known fact that the mouse TNF molecule binds to and activates human TNFRs equally well; thus these animals present with completely normal physiology, yet are able to respond to human TNFR-specific therapeutics. Aside from the study described, these mouse lines are valuable not only to perform deeper basic research on TNFR selective functions, but for applied research towards drug development for other diseases in which TNF is known to play an important role and where TNFR selective targeting might be superior to global TNF inhibition strategies. The availability of these mouse lines facilitates research in preclinical experimental disease models and should substantially reduce the use of higher animal species for drug development in the TNF field.

New research addresses the question of how TNFR2 signalling is neuroprotective. Besides being anti-apoptotic, TNFR signalling also appears to be anti-inflammatory and stimulates remyelination, as shown in earlier studies. Therefore, it seems especially suited for MS treatment. For diseases such as Alzheimer’s, compounds must cross the blood-brain barrier, which is notoriously difficult. But this is currently addressed within a Deltaplan Memorabel project funded by ZonMw, the Netherlands Organization for Health Research and Development, to develop nanoparticles that help medication cross the blood-brain barrier.

Professor Dr Ulrich L M Eisel
University of Groningen
Faculty of Mathematics and Natural Sciences
Groningen Institute of Evolutionary Life Science
Neurobiology Branch
Department of Molecular Neurobiology
+31 50 363 2366
u.l.m.eisel@rug.nl
http://www.rug.nl/staff/u.l.m.eisel/