Contributions
Abstract: EP1426
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - Immunology
Background: While multiple sclerosis (MS) is a disease of the central nervous system (CNS), there is clear evidence of systemic immune activation. For many years it has been considered an autoimmune disorder where auto-aggressive T cells target the CNS causing inflammation. Transendothelial migration (TEM) of leucocytes across the blood brain barrier (BBB) is one of the earliest CNS events leading to brain parenchymal lesions. Most acute lesions in MS are angiocentric and often perivenular. Even when myelin and oligodendrocytes are not present such as in the retina, blood vessel abnormalities have been found. The earliest MRI abnormality in lesion formation is the breakdown of BBB, altogether leading to the view that MS might primarily be a disorder of blood vessels. Targeting events at the BBB e.g. by using natalizumab is a highly effective therapy in relapsing/remitting MS.
Goal: We aim to examine the effect of the disease state and treatment with fingolimod on the TEM of leucocytes across an in vitro BBB.
Methods and results: We collected peripheral blood mononuclear cells (PBMCs) from treated MS patients and studied their migration in an in vitro BBB model (Neuroprobe, USA). Leucocyte number, subsets and phenotype were assessed by flow cytometry. We demonstrated that CD4+ and CD8+
T cells migrated more efficiently across BBB than T cells isolated from healthy subjects. Furthermore, fingolimod treatment significantly reduced migration and adherence of the cells to the membrane, consistent with known effects of fingolimod on rolling, adhesion and transmigration. We also found that there is a higher proportion of BReg cells in the migrating B cell population from healthy and fingolimod treated subjects than in non-treated MS.
Conclusions: While the disease-modifying effects of fingolimod are currently explained by its profound effect on reducing numbers of circulating potentially auto-aggressive lymphocyte populations, we suggest that it may also directly inhibit TEM either by an effect on the residual circulating lymphocyte populations or by modulating brain endothelial function.
Disclosure:
Zinger A.: Nothing to disclose
Hawke S.: Nothing to disclose
Grau G.: Nothing to disclose
Abstract: EP1426
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - Immunology
Background: While multiple sclerosis (MS) is a disease of the central nervous system (CNS), there is clear evidence of systemic immune activation. For many years it has been considered an autoimmune disorder where auto-aggressive T cells target the CNS causing inflammation. Transendothelial migration (TEM) of leucocytes across the blood brain barrier (BBB) is one of the earliest CNS events leading to brain parenchymal lesions. Most acute lesions in MS are angiocentric and often perivenular. Even when myelin and oligodendrocytes are not present such as in the retina, blood vessel abnormalities have been found. The earliest MRI abnormality in lesion formation is the breakdown of BBB, altogether leading to the view that MS might primarily be a disorder of blood vessels. Targeting events at the BBB e.g. by using natalizumab is a highly effective therapy in relapsing/remitting MS.
Goal: We aim to examine the effect of the disease state and treatment with fingolimod on the TEM of leucocytes across an in vitro BBB.
Methods and results: We collected peripheral blood mononuclear cells (PBMCs) from treated MS patients and studied their migration in an in vitro BBB model (Neuroprobe, USA). Leucocyte number, subsets and phenotype were assessed by flow cytometry. We demonstrated that CD4+ and CD8+
T cells migrated more efficiently across BBB than T cells isolated from healthy subjects. Furthermore, fingolimod treatment significantly reduced migration and adherence of the cells to the membrane, consistent with known effects of fingolimod on rolling, adhesion and transmigration. We also found that there is a higher proportion of BReg cells in the migrating B cell population from healthy and fingolimod treated subjects than in non-treated MS.
Conclusions: While the disease-modifying effects of fingolimod are currently explained by its profound effect on reducing numbers of circulating potentially auto-aggressive lymphocyte populations, we suggest that it may also directly inhibit TEM either by an effect on the residual circulating lymphocyte populations or by modulating brain endothelial function.
Disclosure:
Zinger A.: Nothing to disclose
Hawke S.: Nothing to disclose
Grau G.: Nothing to disclose