Final Report Summary - MBFUSEDIT (Molecular Basis for Unwanted Side-Effects During Interferon Therapy)
Type I interferons (IFNs) are widely used for the treatment of patients with hepatitis C and multiple sclerosis (MS). However, common side effects of this therapy are severe neurotoxicity and neuropsychiatric complications such as agitation, depression, anxiety and memory loss in as high as 30-45% of patients. The major gap in our understanding of negative side effects of the IFN-therapy is the identification of the exact mechanism causing these undesirable complications. The goal of the present study was to gain an understanding of the cellular and behavioral consequences of IFN-beta treatment so that targeted interventions can be developed to minimize unwanted side-effects. We have generated mice, which showed specific deletion of the receptor for type I interferons (IFNAR) on neurons, macrophages, glia or endothelia in the CNS. With the combined usage of these mice we were able to answer the central question, how systemically applied IFN-beta mediates its effects in the brain. In a first approach we characterized the effect of chronic, systemic IFN-beta treatment on the expression of prototypic IFN-stimulated genes (ISGs) in the brain. Surprisingly, the majority of ISGs was found in brain endothelial cells. In addition to ISGs, we found a massive upregulation of cytokines like IP10 in brain endothelia. Brain endothelial cells are an essential part of the blood-brain-barrier and, as such, are exposed to proinflammatory mediators as well as danger signals during infections, and therefore might function as decisive cells mediating IFN-mediated sickness behavior. Animals lacking the receptor for IP10 (CXCR3 knock out mice) showed no signs of depressive-like behavior or memory impairment in response to IFN-beta treatment. We assumed that IP10 would be released from brain endothelia and would modulate neuronal signaling in brain areas responsible for mood and cognitive processing. Activity-dependent changes in synaptic strength in the hippocampus are thought to underlie memory processes and other adaptive responses of the nervous system including mood stability. Electrophysiological recordings from hippocampal brain slices of wild-type mice showed that long-term potentiation (LTP), a form of synaptic plasticity, is suppressed in the hippocampus following IP10 application. Identical results were obtained when recordings were repeated in the hippocampus of wild-type mice in vivo. The observed impairment of neuronal plasticity in the presence of IP10 nicely supports the idea that IP10 released in response to IFN-beta is responsible for the corresponding behavioral changes. In summary, our study provides evidence for the importance of brain endothelial cells in the communication between CNS and the immune system, and demonstrates tissue specific IFNAR1 engagement during sickness behavior. By the identification of the IFN-induced IP10/CXCR3 axis, we offer new drug targets for the management of cognitive and behavioral impairment during type I IFN therapy.
The fellow is now head of a research group consisting of a PhD-student, a master student and a MD-student. For autumn 2015, two more master students will start their theses in his group. Meanwhile, the fellow is fully integrated and valuable part of the institute. Besides teaching medical students and giving seminars also to other departments, he is involved in training students, even from other institutes, in animal behavior. His integration is further documented by the invitation to join a Transregio funding initiative between institutes in Freiburg and Berlin. All these activities should and will enable the fellow to pursue his next career step towards a permanent position.
Website:
http://www.uniklinik-freiburg.de/neuropathologie/forschung/cellular-and-molecular-neuroimmunology-dr-t-blank.html
The fellow is now head of a research group consisting of a PhD-student, a master student and a MD-student. For autumn 2015, two more master students will start their theses in his group. Meanwhile, the fellow is fully integrated and valuable part of the institute. Besides teaching medical students and giving seminars also to other departments, he is involved in training students, even from other institutes, in animal behavior. His integration is further documented by the invitation to join a Transregio funding initiative between institutes in Freiburg and Berlin. All these activities should and will enable the fellow to pursue his next career step towards a permanent position.
Website:
http://www.uniklinik-freiburg.de/neuropathologie/forschung/cellular-and-molecular-neuroimmunology-dr-t-blank.html
