Tumor 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 failed in clinical trials of MS. Two research groups, one at the Institute of Cell Biology and Immunology of University of Stuttgart (led by Profs. Kontermann and Pfizenmaier) and the other at University of Groningen, NL (led by Prof. Eisel) have shown in previous collaborative research with cell and animal models that failure of anti TNF therapeutics in neurologic disorders is most likely due to antithetic effects of the two TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. In the 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 disease 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 behavioral studies, respectively. Most important, neuroprotection mediated by the TNFR1 antagonist is abrogated by simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signaling and uncover why anti-TNF drugs failed in treatment of neurodegenerative diseases. The implications of this finding are far reaching.

Tumor 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 failed in clinical trials of MS. Two research groups, one at the Institute of Cell Biology and Immunology of University of Stuttgart (led by Profs. Kontermann and Pfizenmaier) and the other at University of Groningen, NL (led by Prof. Eisel) have shown in previous collaborative research with cell and animal models that failure of anti TNF therapeutics in neurologic disorders is most likely due to antithetic effects of the two TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. In the 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 disease 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 behavioral studies, respectively. Most important, neuroprotection mediated by the TNFR1 antagonist is abrogated by simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signaling and uncover why anti-TNF drugs failed in treatment of neurodegenerative diseases. The implications of this finding are far reaching.

Tumor 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 failed in clinical trials of MS. Two research groups, one at the Institute of Cell Biology and Immunology of University of Stuttgart (led by Profs. Kontermann and Pfizenmaier) and the other at University of Groningen, NL (led by Prof. Eisel) have shown in previous collaborative research with cell and animal models that failure of anti TNF therapeutics in neurologic disorders is most likely due to antithetic effects of the two TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. In the 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 disease 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 behavioral studies, respectively. Most important, neuroprotection mediated by the TNFR1 antagonist is abrogated by simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signaling and uncover why anti-TNF drugs failed in treatment of neurodegenerative diseases. The implications of this finding are far reaching.

Tumor 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 failed in clinical trials of MS. Two research groups, one at the Institute of Cell Biology and Immunology of University of Stuttgart (led by Profs. Kontermann and Pfizenmaier) and the other at University of Groningen, NL (led by Prof. Eisel) have shown in previous collaborative research with cell and animal models that failure of anti TNF therapeutics in neurologic disorders is most likely due to antithetic effects of the two TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. In the 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 disease 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 behavioral studies, respectively. Most important, neuroprotection mediated by the TNFR1 antagonist is abrogated by simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signaling and uncover why anti-TNF drugs failed in treatment of neurodegenerative diseases. The implications of this finding are far reaching.

Tumor 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 failed in clinical trials of MS. Two research groups, one at the Institute of Cell Biology and Immunology of University of Stuttgart (led by Profs. Kontermann and Pfizenmaier) and the other at University of Groningen, NL (led by Prof. Eisel) have shown in previous collaborative research with cell and animal models that failure of anti TNF therapeutics in neurologic disorders is most likely due to antithetic effects of the two TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. In the 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 disease 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 behavioral studies, respectively. Most important, neuroprotection mediated by the TNFR1 antagonist is abrogated by simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signaling and uncover why anti-TNF drugs failed in treatment of neurodegenerative diseases. The implications of this finding are far reaching.