Author Of 2 Presentations
P0103 - Liothyronine treatment of MS patients alters proteins in CSF related to angiogenesis and immune function (ID 438)
Abstract
Background
Thyroid hormones have effects on a variety of glial and immune cell populations that appear to be involved in the pathogenesis of multiple sclerosis (MS). Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) may have the potential to induce reparative mechanisms and limit neurodegeneration in MS.
Objectives
To utilize proteomics to assess the effect of liothyronine treatment on the cerebrospinal fluid (CSF) proteome in MS.
Methods
We utilized CSF collected from 18 patients with MS enrolled in a single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Participants continued their maintenance MS immune therapies during the study. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. CSF was collected at baseline and end of study (24 weeks) as an exploratory outcome for treatment response. SOMAscan platform (DNA aptamer based detection of proteins) was used to detect and quantify a panel of 1314 proteins in the CSF.
Results
Study participants had a mean age of 45.9 ± 8.8 years, F:M ratio of 7:9, relapsing disease (11/16), mean disease duration of 9 years and median EDSS of 3.5. Of the measured proteins, 46 changed (19 increased and 27 decreased) over the course of the study (p<0.05). These included proteins related to immune function such as TACI, NKp46, IgA and IgD and angiogenesis such as Cadherin-5, sTIE-1 and ANGPT2. Enrichment analyses using PANTHER and STRING databases noted that the biological processes that were over-represented included – angiogenesis and innate and adaptive immune function. Angiogenesis related proteins predominantly demonstrated an increase with liothyronine treatment while the majority of immune related proteins decreased with treatment.
Conclusions
Changes in CSF proteins involved in central nervous system immune cell function and promotion of angiogenesis were seen with a short course of liothyronine treatment in people with MS. A larger clinical trial would help determine whether these observed changes have a biological effect that is clinically meaningful.
P0404 - The Bruton’s tyrosine kinase inhibitor evobrutinib ameliorates meningeal inflammation in experimental autoimmune encephalomyelitis (ID 1354)
Abstract
Background
Leptomeningeal inflammation in multiple sclerosis (MS) is associated with worse clinical outcomes and greater cortical pathology. Both B cells and myeloid cells are found in areas of meningeal inflammation. We previously demonstrated that, in the relapsing–remitting encephalomyelitis (EAE) model in SJL mice, ultra-high field contrast-enhanced magnetic resonance imaging (MRI) could identify and track areas of meningeal inflammation. Bruton’s tyrosine kinase (BTK) mediates signaling through B cell receptor and Fc receptor pathways and leads to B cell and myeloid cell activation. We therefore hypothesized that a BTK inhibitor could target meningeal inflammation in EAE.
Objectives
To test the effect of evobrutinib, a highly selective BTK inhibitor, as a potential therapy targeting meningeal inflammation in a mouse model of MS.
Methods
We immunized 7- to 8-week-old female SJL/J mice with proteolipid protein 139–151 peptide and complete Freund’s adjuvant to induce EAE. Animals were weighed and disease severity was scored starting at 7 days post-immunization; at 6 weeks they underwent Gadolinium-enhanced MRI. Mice demonstrating the presence of meningeal contrast enhancement were randomized to receive daily oral doses by gavage of evobrutinib (10 mg/kg) or vehicle control between Weeks 6–10 post-immunization. MRI was repeated at Weeks 8 and 10 to assess meningeal inflammation, and brain tissues were collected for histopathological analysis.
Results
At baseline, both vehicle (n=16) and evobrutinib (n=19) groups had a similar number of areas of meningeal contrast enhancement (median: 10.5 vs 11; p=0.25). Following treatment, a greater reduction in the number of areas of meningeal contrast enhancement was identified in the evobrutinib group vs the vehicle group (median change: -3 vs 0.5; p=0.003). A significant decrease in B cells in areas of meningeal inflammation in the evobrutinib group compared to the vehicle group was noted. Also, astrocytosis in the adjacent cortex was reduced in the evobrutinib group compared with vehicle.
Conclusions
An amelioration of established meningeal inflammation, as assessed by imaging and pathological measures, in a relapsing–remitting EAE model was observed with evobrutinib treatment, suggesting the potential utility of this agent to target this phenomenon in MS patients.
Presenter Of 2 Presentations
P0103 - Liothyronine treatment of MS patients alters proteins in CSF related to angiogenesis and immune function (ID 438)
Abstract
Background
Thyroid hormones have effects on a variety of glial and immune cell populations that appear to be involved in the pathogenesis of multiple sclerosis (MS). Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) may have the potential to induce reparative mechanisms and limit neurodegeneration in MS.
Objectives
To utilize proteomics to assess the effect of liothyronine treatment on the cerebrospinal fluid (CSF) proteome in MS.
Methods
We utilized CSF collected from 18 patients with MS enrolled in a single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Participants continued their maintenance MS immune therapies during the study. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. CSF was collected at baseline and end of study (24 weeks) as an exploratory outcome for treatment response. SOMAscan platform (DNA aptamer based detection of proteins) was used to detect and quantify a panel of 1314 proteins in the CSF.
Results
Study participants had a mean age of 45.9 ± 8.8 years, F:M ratio of 7:9, relapsing disease (11/16), mean disease duration of 9 years and median EDSS of 3.5. Of the measured proteins, 46 changed (19 increased and 27 decreased) over the course of the study (p<0.05). These included proteins related to immune function such as TACI, NKp46, IgA and IgD and angiogenesis such as Cadherin-5, sTIE-1 and ANGPT2. Enrichment analyses using PANTHER and STRING databases noted that the biological processes that were over-represented included – angiogenesis and innate and adaptive immune function. Angiogenesis related proteins predominantly demonstrated an increase with liothyronine treatment while the majority of immune related proteins decreased with treatment.
Conclusions
Changes in CSF proteins involved in central nervous system immune cell function and promotion of angiogenesis were seen with a short course of liothyronine treatment in people with MS. A larger clinical trial would help determine whether these observed changes have a biological effect that is clinically meaningful.
P0404 - The Bruton’s tyrosine kinase inhibitor evobrutinib ameliorates meningeal inflammation in experimental autoimmune encephalomyelitis (ID 1354)
Abstract
Background
Leptomeningeal inflammation in multiple sclerosis (MS) is associated with worse clinical outcomes and greater cortical pathology. Both B cells and myeloid cells are found in areas of meningeal inflammation. We previously demonstrated that, in the relapsing–remitting encephalomyelitis (EAE) model in SJL mice, ultra-high field contrast-enhanced magnetic resonance imaging (MRI) could identify and track areas of meningeal inflammation. Bruton’s tyrosine kinase (BTK) mediates signaling through B cell receptor and Fc receptor pathways and leads to B cell and myeloid cell activation. We therefore hypothesized that a BTK inhibitor could target meningeal inflammation in EAE.
Objectives
To test the effect of evobrutinib, a highly selective BTK inhibitor, as a potential therapy targeting meningeal inflammation in a mouse model of MS.
Methods
We immunized 7- to 8-week-old female SJL/J mice with proteolipid protein 139–151 peptide and complete Freund’s adjuvant to induce EAE. Animals were weighed and disease severity was scored starting at 7 days post-immunization; at 6 weeks they underwent Gadolinium-enhanced MRI. Mice demonstrating the presence of meningeal contrast enhancement were randomized to receive daily oral doses by gavage of evobrutinib (10 mg/kg) or vehicle control between Weeks 6–10 post-immunization. MRI was repeated at Weeks 8 and 10 to assess meningeal inflammation, and brain tissues were collected for histopathological analysis.
Results
At baseline, both vehicle (n=16) and evobrutinib (n=19) groups had a similar number of areas of meningeal contrast enhancement (median: 10.5 vs 11; p=0.25). Following treatment, a greater reduction in the number of areas of meningeal contrast enhancement was identified in the evobrutinib group vs the vehicle group (median change: -3 vs 0.5; p=0.003). A significant decrease in B cells in areas of meningeal inflammation in the evobrutinib group compared to the vehicle group was noted. Also, astrocytosis in the adjacent cortex was reduced in the evobrutinib group compared with vehicle.
Conclusions
An amelioration of established meningeal inflammation, as assessed by imaging and pathological measures, in a relapsing–remitting EAE model was observed with evobrutinib treatment, suggesting the potential utility of this agent to target this phenomenon in MS patients.