Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition
| Autor: | Peter A. Calabresi, Martina Absinta, Arthur Anthony Reyes, Sol Kim, Peter C.M. van Zijl, Roland Grenningloh, Ursula Boschert, Pavan Bhargava, Jiangyang Zhang, Carlos Pardo-Villamizar |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Encephalomyelitis Autoimmune Experimental Inflammation Fluid-attenuated inversion recovery Mice 03 medical and health sciences Meninges 0302 clinical medicine Piperidines Agammaglobulinaemia Tyrosine Kinase medicine Animals Bruton's tyrosine kinase CXCL13 Follicular dendritic cells medicine.diagnostic_test biology business.industry Multiple sclerosis Experimental autoimmune encephalomyelitis Brain Magnetic resonance imaging Original Articles medicine.disease Pyrimidines 030104 developmental biology Lymphatic system biology.protein Female Neurology (clinical) medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Brain |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awab045 |
| Popis: | Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identification of this process in multiple sclerosis patients using post-contrast FLAIR imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 Tesla) MRI to perform post-contrast FLAIR imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced using immunization with proteolipid protein peptide (PLP139-151) and complete Freund’s adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time-points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which identified dense cellular infiltrates corresponding to areas of contrast-enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas – presence of peripheral node addressin (PNAd) positive structures, CXCL13 producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib (a Bruton’s tyrosine kinase inhibitor) for a period of 4 weeks. These mice underwent serial imaging and we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We utilized ultra-high field MRI imaging to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis and then utilized this model to identify Bruton’s tyrosine kinase inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation. |
| Databáze: | OpenAIRE |
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