High dose vitamin D worsens experimental CNS autoimmune disease by raising T cell-excitatory calcium
ECTRIMS Online Library. Häusler D. 09/13/19; 279543; 281
Darius Häusler
Darius Häusler
Contributions
Abstract

Abstract: 281

Type: Scientific Session

Abstract Category: Therapy - Immunomodulation/Immunosuppression

D. Häusler1, S. Torke1, E. Peelen2, T. Bertsch3, M. Djukic1,4, R. Nau1,4, C. Larochelle2, S.S. Zamvil5, W. Brück1, M.S. Weber1,6

1Institute of Neuropathology, Universitaetsmedizin Goettingen, Goettingen, Germany, 2Department of Neurosciences, Centre de Recherche de l'Université de Montréal (CRCHUM), Montréal, QC, Canada, 3Institute of Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, General Hospital Nuremberg, Paracelsus Medical University, Nuremberg, 4Department of Geriatrics, Evangelisches Krankenhaus Göttingen-Weende, Goettingen, Germany, 5Department of Neurology, University of California, San Francisco, CA, United States, 6Department of Neurology, Universitaetsmedizin Goettingen, Goettingen, Germany

Background: As low serum vitamin D has been associated with higher relapse rate and earlier disability in multiple sclerosis (MS), patients are commonly supplemented with the vitamin D precursor cholecalciferol. To model consequences of this practice, we tested long-term vitamin D supplementation at distinct doses in experimental autoimmune encephalomyelitis (EAE), the animal model of MS.
Methods: Mice were fed continuously with a low, medium or high cholecalciferol diet to generate serum levels of 25-(OH) vitamin D representing vitamin D deficiency, normal ranges, or its excessive supplementation in MS followed by immunization with myelin oligodendrocyte glycoprotein (MOG) p35-55. Clinical symptoms were monitored, central nervous system (CNS) infiltration quantified and peripheral T cells / myeloid APCs phenotypically analyzed for expression of activation markers, co-stimulatory molecules and secretion of cytokines.
Results: Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent EAE, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/L developed fulminant EAE with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcemia associated with a T cell phenotype prone to pro-inflammatory activation. Raising murine serum calcium level by calcium gluconate injections resulted in increased expression of activation markers on CD4+ and CD8+ T cells confirming that this effect occurs in vivo independent of vitamin D. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model.
Conclusion: These findings highlight excessive vitamin D supplementation and resulting hypercalcemia as novel risk factors promoting worsening of CNS demyelinating disease. Our data caution that in light of the currently limited information on a direct beneficial effect of vitamin D in MS, MS patients may be at danger of experiencing untoward immunological and/or clinical effects when vitamin D is supplemented excessively.
Disclosure: Darius Häusler: receives research support from the Startförderung Programm of the University of Göttingen. Sebastian Torke: Nothing to disclose. Evelyn Peelen: nothing to disclose. Thomas Bertsch: nothing to disclose. Marija Djukic: nothing to disclose. Roland Nau: nothing to disclose. Catherine Larochelle: nothing to disclose. Scott S. Zamvil: nothing to disclose. Wolfgang Brück: received honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis. Member of scientific advisory boards for Teva Pharma, Biogen, Novartis, Celgene, Medday and Genzyme. Receives research support from Teva Pharma, Biogen, Medday, Genzyme and Novartis. Serves on the editorial boards of Neuropathology and Applied Neurobiology, Therapeutic Advances in Neurological Diseases and Multiple Sclerosis International. Martin S. Weber: Editor for PLoS One. Received travel funding and/or speaker honoraria from Biogen-Idec, EMD Serono, Novartis, Roche and Bayer. Receives research support from the National Multiple Sclerosis Society (NMSS; PP1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, EMD Serono, TEVA, Biogen-Idec, Roche and the ProFutura Programm of the Universitätsmedizin Göttingen.

Abstract: 281

Type: Scientific Session

Abstract Category: Therapy - Immunomodulation/Immunosuppression

D. Häusler1, S. Torke1, E. Peelen2, T. Bertsch3, M. Djukic1,4, R. Nau1,4, C. Larochelle2, S.S. Zamvil5, W. Brück1, M.S. Weber1,6

1Institute of Neuropathology, Universitaetsmedizin Goettingen, Goettingen, Germany, 2Department of Neurosciences, Centre de Recherche de l'Université de Montréal (CRCHUM), Montréal, QC, Canada, 3Institute of Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, General Hospital Nuremberg, Paracelsus Medical University, Nuremberg, 4Department of Geriatrics, Evangelisches Krankenhaus Göttingen-Weende, Goettingen, Germany, 5Department of Neurology, University of California, San Francisco, CA, United States, 6Department of Neurology, Universitaetsmedizin Goettingen, Goettingen, Germany

Background: As low serum vitamin D has been associated with higher relapse rate and earlier disability in multiple sclerosis (MS), patients are commonly supplemented with the vitamin D precursor cholecalciferol. To model consequences of this practice, we tested long-term vitamin D supplementation at distinct doses in experimental autoimmune encephalomyelitis (EAE), the animal model of MS.
Methods: Mice were fed continuously with a low, medium or high cholecalciferol diet to generate serum levels of 25-(OH) vitamin D representing vitamin D deficiency, normal ranges, or its excessive supplementation in MS followed by immunization with myelin oligodendrocyte glycoprotein (MOG) p35-55. Clinical symptoms were monitored, central nervous system (CNS) infiltration quantified and peripheral T cells / myeloid APCs phenotypically analyzed for expression of activation markers, co-stimulatory molecules and secretion of cytokines.
Results: Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent EAE, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/L developed fulminant EAE with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcemia associated with a T cell phenotype prone to pro-inflammatory activation. Raising murine serum calcium level by calcium gluconate injections resulted in increased expression of activation markers on CD4+ and CD8+ T cells confirming that this effect occurs in vivo independent of vitamin D. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model.
Conclusion: These findings highlight excessive vitamin D supplementation and resulting hypercalcemia as novel risk factors promoting worsening of CNS demyelinating disease. Our data caution that in light of the currently limited information on a direct beneficial effect of vitamin D in MS, MS patients may be at danger of experiencing untoward immunological and/or clinical effects when vitamin D is supplemented excessively.
Disclosure: Darius Häusler: receives research support from the Startförderung Programm of the University of Göttingen. Sebastian Torke: Nothing to disclose. Evelyn Peelen: nothing to disclose. Thomas Bertsch: nothing to disclose. Marija Djukic: nothing to disclose. Roland Nau: nothing to disclose. Catherine Larochelle: nothing to disclose. Scott S. Zamvil: nothing to disclose. Wolfgang Brück: received honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis. Member of scientific advisory boards for Teva Pharma, Biogen, Novartis, Celgene, Medday and Genzyme. Receives research support from Teva Pharma, Biogen, Medday, Genzyme and Novartis. Serves on the editorial boards of Neuropathology and Applied Neurobiology, Therapeutic Advances in Neurological Diseases and Multiple Sclerosis International. Martin S. Weber: Editor for PLoS One. Received travel funding and/or speaker honoraria from Biogen-Idec, EMD Serono, Novartis, Roche and Bayer. Receives research support from the National Multiple Sclerosis Society (NMSS; PP1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, EMD Serono, TEVA, Biogen-Idec, Roche and the ProFutura Programm of the Universitätsmedizin Göttingen.

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