Contributions
Abstract: P430
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background: Progressive forms of multiple sclerosis (PMS) are characterized by consistently increasing disability and often respond poorly to established immunomodulatory therapies, although histopathological features indicative of inflammation are usually detectable (Ontaneda et al., 2017; Lancet. 389:1357-1366). Consequently, the pathogenic relevance of inflammation and the reason for failure of immune therapies in PMS are unclear.
Objectives: We previously generated novel mouse models carrying point mutations in the PLP1 gene that have been described in PMS patients. The PLPmut mice reflect important aspect of PMS and we could unequivocally demonstrate a detrimental pathogenic impact of chronic secondary neuroinflammation in the models by cross-breeding them with distinct knockout mice to abolish or enhance adaptive immune reactions (Groh et al., 2016; Human Molecular Genetics. 25:4686-4702). Here we tested the efficacy of the clinically approved immunomodulatory compound teriflunomide to attenuate or prevent neuroinflammation-related neural damage in the mouse models.
Methods: PLPmut mice were treated for several months with teriflunomide (10mg/kg/day) ad libitum in drinking water and monitored with non-invasive methods like optical coherence tomography (OCT). Subsequently, the respective treatment and control groups were analysed by flow cytometry, immunohistochemistry, histology and electron microscopy.
Results: The long-term treatment with teriflunomide significantly attenuated neuroinflammation in PLPmut mice. This resulted in reduced axonal perturbation, neuron loss and - in case of the OCT analysis - reduced retinal thinning. Early treatment in young and mildly affected mutants was more effective than later treatment at advanced disease stages. The treatment did not cause obvious deleterious side effects and treatment termination did not result in a rebound effect.
Conclusions: Our data corroborate the pathogenic relevance of secondary neuroinflammation in the PMS-related mouse models with primary oligodendroglial myelin defects. They also show that specific immunomodulatory compounds like teriflunomide can significantly ameliorate disease progression, especially when applied in early stages. These findings might be of high relevance regarding putative treatment approaches for PMS and other chronic progressive disorders of the CNS accompanied by secondary neuroinflammation.
Disclosure: This study was supported by the Interdisciplinary Centre of Clinical Research of the University of Wuerzburg (IZKF A-168) and Sanofi Genzyme (Cambridge, USA).
Abstract: P430
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background: Progressive forms of multiple sclerosis (PMS) are characterized by consistently increasing disability and often respond poorly to established immunomodulatory therapies, although histopathological features indicative of inflammation are usually detectable (Ontaneda et al., 2017; Lancet. 389:1357-1366). Consequently, the pathogenic relevance of inflammation and the reason for failure of immune therapies in PMS are unclear.
Objectives: We previously generated novel mouse models carrying point mutations in the PLP1 gene that have been described in PMS patients. The PLPmut mice reflect important aspect of PMS and we could unequivocally demonstrate a detrimental pathogenic impact of chronic secondary neuroinflammation in the models by cross-breeding them with distinct knockout mice to abolish or enhance adaptive immune reactions (Groh et al., 2016; Human Molecular Genetics. 25:4686-4702). Here we tested the efficacy of the clinically approved immunomodulatory compound teriflunomide to attenuate or prevent neuroinflammation-related neural damage in the mouse models.
Methods: PLPmut mice were treated for several months with teriflunomide (10mg/kg/day) ad libitum in drinking water and monitored with non-invasive methods like optical coherence tomography (OCT). Subsequently, the respective treatment and control groups were analysed by flow cytometry, immunohistochemistry, histology and electron microscopy.
Results: The long-term treatment with teriflunomide significantly attenuated neuroinflammation in PLPmut mice. This resulted in reduced axonal perturbation, neuron loss and - in case of the OCT analysis - reduced retinal thinning. Early treatment in young and mildly affected mutants was more effective than later treatment at advanced disease stages. The treatment did not cause obvious deleterious side effects and treatment termination did not result in a rebound effect.
Conclusions: Our data corroborate the pathogenic relevance of secondary neuroinflammation in the PMS-related mouse models with primary oligodendroglial myelin defects. They also show that specific immunomodulatory compounds like teriflunomide can significantly ameliorate disease progression, especially when applied in early stages. These findings might be of high relevance regarding putative treatment approaches for PMS and other chronic progressive disorders of the CNS accompanied by secondary neuroinflammation.
Disclosure: This study was supported by the Interdisciplinary Centre of Clinical Research of the University of Wuerzburg (IZKF A-168) and Sanofi Genzyme (Cambridge, USA).