Contributions
Abstract: EP1466
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background: Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the TGF-beta superfamily. In the adult brain, BMPs modulate neurogenesis, favour astrogliogenesis and inhibit oligodendrogenesis, and they are also involved in demyelination processes. Moreover, BMPs have been proposed as regulators of the immune response.
Objective: We aimed to test the therapeutic potential of two small molecules that inhibit BMP signaling (dorsomorphin and its analogue DMH1) in MOG-induced experimental autoimmune encephalomyelitis (EAE). Disclosure of conflict of interest: HE, LC-B, CC, GR-V, CE declare no competing financial interests.
XM has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
Methods: EAE was induced in 8-week old C57BL6/J female mice with the 35-55 MOG peptide. Mice were randomized once EAE clinical signs were established, and animals were treated daily with 3mg/kg dorsomorphin (n=13), 5mg/kg DMH1 (n=13), or vehicle (DMSO; n=12). At the end of the experiment (day 29-33 postimmunization), we quantified inflammation and demyelination in the CNS. We evaluated the proliferative capacity of splenocytes upon antigen-specific (MOG35-55) or polyclonal (phytohematoagglutinin or PHA) stimulus, and the frequency of peripheral immune populations (T cells, B cells and myeloid cells) by flow cytometry.
Results: Therapeutic treatment with dorsomorphin ameliorated EAE outcome measured as the area under the curve (AUC) of the mean daily clinical score for each group (vehicle group: 68.33±10.65 and dorsomorphin group: 54.52±19.27; p=0.039). Treatment with DMH1 also resulted in a better EAE outcome (AUC: 52.65±18.34) compared with vehicle-treated mice (p=0.017). Conversely, we did not find differences in the proliferative response of splenocytes upon stimulation with MOG35-55 or PHA in vehicle-treated mice compared with dorsomorphin- and DMH1-treated groups. Because DMH1 is a more specific BMP-signaling inhibitor, we performed the histopathological study and the evaluation of the frequency of peripheral immune cells in DMH1-treated mice and vehicle-treated mice. DMH1-treated mice presented less inflammation in the CNS (inflammation score for vehicle group: 3.36±0.67, and for DMH1 group: 2.69±0.85; p= 0.047), and also presented a lower frequency of myeloid cells in the spleen (vehicle group: 70.86±6.72% and DMH1 group: 61.70±4.77%); p=0.015). Moreover, macrophages were also decreased in the DMH1 group although no statistical significance was reached (vehicle group: 16.13±6.57% and DMH1 group: 10.11±3.34%; p=0.056).
Conclusion: These data points to the specific inhibition of BMP signaling as a novel potential therapeutic target for MS.
Disclosure: Founding source:
Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Spain (PI12/02144)
Abstract: EP1466
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background: Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the TGF-beta superfamily. In the adult brain, BMPs modulate neurogenesis, favour astrogliogenesis and inhibit oligodendrogenesis, and they are also involved in demyelination processes. Moreover, BMPs have been proposed as regulators of the immune response.
Objective: We aimed to test the therapeutic potential of two small molecules that inhibit BMP signaling (dorsomorphin and its analogue DMH1) in MOG-induced experimental autoimmune encephalomyelitis (EAE). Disclosure of conflict of interest: HE, LC-B, CC, GR-V, CE declare no competing financial interests.
XM has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
Methods: EAE was induced in 8-week old C57BL6/J female mice with the 35-55 MOG peptide. Mice were randomized once EAE clinical signs were established, and animals were treated daily with 3mg/kg dorsomorphin (n=13), 5mg/kg DMH1 (n=13), or vehicle (DMSO; n=12). At the end of the experiment (day 29-33 postimmunization), we quantified inflammation and demyelination in the CNS. We evaluated the proliferative capacity of splenocytes upon antigen-specific (MOG35-55) or polyclonal (phytohematoagglutinin or PHA) stimulus, and the frequency of peripheral immune populations (T cells, B cells and myeloid cells) by flow cytometry.
Results: Therapeutic treatment with dorsomorphin ameliorated EAE outcome measured as the area under the curve (AUC) of the mean daily clinical score for each group (vehicle group: 68.33±10.65 and dorsomorphin group: 54.52±19.27; p=0.039). Treatment with DMH1 also resulted in a better EAE outcome (AUC: 52.65±18.34) compared with vehicle-treated mice (p=0.017). Conversely, we did not find differences in the proliferative response of splenocytes upon stimulation with MOG35-55 or PHA in vehicle-treated mice compared with dorsomorphin- and DMH1-treated groups. Because DMH1 is a more specific BMP-signaling inhibitor, we performed the histopathological study and the evaluation of the frequency of peripheral immune cells in DMH1-treated mice and vehicle-treated mice. DMH1-treated mice presented less inflammation in the CNS (inflammation score for vehicle group: 3.36±0.67, and for DMH1 group: 2.69±0.85; p= 0.047), and also presented a lower frequency of myeloid cells in the spleen (vehicle group: 70.86±6.72% and DMH1 group: 61.70±4.77%); p=0.015). Moreover, macrophages were also decreased in the DMH1 group although no statistical significance was reached (vehicle group: 16.13±6.57% and DMH1 group: 10.11±3.34%; p=0.056).
Conclusion: These data points to the specific inhibition of BMP signaling as a novel potential therapeutic target for MS.
Disclosure: Founding source:
Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Spain (PI12/02144)