ABSTRACT
OBJECTIVE: To evaluate the influence of Fingolimod treatment on B-cell subset composition and function in multiple sclerosis patients and its potential clinical relevance. METHODS: Subset composition and cytokine production of B cells derived from peripheral blood mononuclear cells from multiple sclerosis patients under Fingolimod treatment, untreated multiple sclerosis patients and healthy controls were analyzed by flow cytometry and ELISA. Migration of lymphocyte subsets across primary human brain microvascular endothelial cells was assessed in an in vitro transmigration assay. Cell numbers and composition of B-cell subsets in cerebrospinal fluid and peripheral blood were determined by flow cytometry. Regulatory B-cell frequencies were correlated with parameters of disease stability. RESULTS: Within the peripheral B-cell compartment of Fingolimod-treated patients, the proportion of regulatory B cells (CD38(+)CD27(-)CD24(+)CD5(+)) was significantly increased as compared to treatment-naïve multiple sclerosis patients and to healthy controls, and significantly more regulatory B cells produced Interleukin-10. Fingolimod treatment enhanced the capacity of regulatory B cells to transmigrate across brain endothelial cells in an in vitro model of the blood-brain-barrier. In line with these findings, the cerebrospinal fluid/blood ratio of total B cells and regulatory B cells was strongly increased by Fingolimod treatment, and patients exhibited increased regulatory B-cell frequencies in the cerebrospinal fluid. Finally, elevated regulatory B-cell percentages in the periphery significantly correlated with clinical and paraclinical disease stability. INTERPRETATION: These data suggest a novel and as yet unrecognized role of Fingolimod in correction of the imbalance between regulatory and effector B-cell functions in multiple sclerosis both by direct effects and indirect partitioning effects on B-cell subpopulations.
ABSTRACT
Despite early antiviral treatment, herpes simples virus encephalitis (HSVE) still remains a life-threatening sporadic disease with high mortality and morbidity. In patients and in experimental disease, chronic progressive magnetic resonance imaging (MRI) abnormalities have been found even after antiviral therapy. Secondary autoimmune-mediated and not directly virus-mediated mechanisms might play a key role for the outcome of disease. This study aimed to evaluate a possible beneficial effect of a therapy of acyclovir and corticosteroids versus acyclovir only. In a mouse model of HSVE (intranasal inoculation with 10(5) pfu [plaque-forming units] of HSV-1 strain F), a long-term MRI study was realized. Cranial MRI was performed serially at days 2, 7, 14, 21, 60, and 180 in different therapy groups: 1, saline; 2, acyclovir; 3, acyclovir, subsequently methylprednisolone; 4, sham-infected with saline. Brain viral load peaked at day 7 to decline thereafter to a low baseline value. Viral load in group 1 was significantly higher than in animals with antiviral therapy. In group 4, no viral DNA was detectable. Viral load did not differ significantly between acyclovir and acyclovir/corticosteroid-treated groups, suggesting that the use of corticosteroids in addition to acyclovir does not increase viral burden. MRI findings in untreated and acyclovir-treated animals revealed chronic progressive changes. In contrast, there was a significant reduction of the severity of long-term MRI abnormalities in acyclovir/corticosteroid-treated animals. With respect to abnormal MRI findings, this study demonstrates a clear beneficial effect of an acyclovir and corticosteroid therapy without influencing brain viral load.
