A H Cross1, L Piccio1, E E Longbrake1, M J Ramsbottom1, C Cantoni1, L Ghezzi1,2. 1. Department of Neurology, Washington University in St. Louis, St. Louis, Missouri. 2. Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
Abstract
BACKGROUND: Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated multiple sclerosis (MS) patients. OBJECTIVE: To phenotypically characterize circulating leukocytes in DMF-treated MS patients. METHODS: Cross-sectional observational comparisons of peripheral blood from DMF-treated MS patients (n = 17 lymphopenic and n = 24 non-lymphopenic), untreated MS patients (n = 17) and healthy controls (n = 23); immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients. RESULTS: Lymphopenic DMF-treated patients had significantly fewer circulating CD8(+) and CD4(+) T cells, CD56(dim) natural killer (NK) cells, CD19(+) B cells and plasmacytoid dendritic cells when compared to controls. CXCR3(+) and CCR6(+) expression was disproportionately reduced among CD4(+) T cells, while the proportion of T-regulatory (T-reg) cells was unchanged. DMF did not affect circulating CD56(hi) NKcells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of naïve T cells compared to the controls. CONCLUSIONS: DMF shifts the immunophenotypes of circulating T cells, causing a reduction of memory cells and a relative expansion of naïve cells, regardless of the absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenic patients had a disproportionate loss of CD8(+) T-cells, which may affect their immunocompetence.
BACKGROUND:Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated multiple sclerosis (MS) patients. OBJECTIVE: To phenotypically characterize circulating leukocytes in DMF-treated MSpatients. METHODS: Cross-sectional observational comparisons of peripheral blood from DMF-treated MSpatients (n = 17 lymphopenic and n = 24 non-lymphopenic), untreated MSpatients (n = 17) and healthy controls (n = 23); immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients. RESULTS:Lymphopenic DMF-treatedpatients had significantly fewer circulating CD8(+) and CD4(+) T cells, CD56(dim) natural killer (NK) cells, CD19(+) B cells and plasmacytoid dendritic cells when compared to controls. CXCR3(+) and CCR6(+) expression was disproportionately reduced among CD4(+) T cells, while the proportion of T-regulatory (T-reg) cells was unchanged. DMF did not affect circulating CD56(hi) NKcells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of naïve T cells compared to the controls. CONCLUSIONS:DMF shifts the immunophenotypes of circulating T cells, causing a reduction of memory cells and a relative expansion of naïve cells, regardless of the absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenicpatients had a disproportionate loss of CD8(+) T-cells, which may affect their immunocompetence.
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