title: Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis.
abstract: OBJECTIVE
  To examine the mechanism underlying the preferential CD8+vs CD4+T-cell lymphopenia induced by dimethyl fumarate (DMF) treatment of MS.
  
  
  METHODS
  Total lymphocyte counts and comprehensive T-cell subset analyses were performed in high-quality samples obtained from patients with MS prior to and serially following DMF treatment initiation. Random coefficient mixed-effects analysis was used to model the trajectory of T-cell subset losses in vivo. Survival and apoptosis of distinct T-cell subsets were assessed following in vitro exposure to DMF.
  
  
  RESULTS
  Best-fit modeling indicated that the DMF-induced preferential reductions in CD8+vs CD4+T-cell counts nonetheless followed similar depletion kinetics, suggesting a similar rather than distinct mechanism involved in losses of both the CD8+and CD4+T cells. In vitro, DMF exposure resulted in dose-dependent reductions in T-cell survival, which were found to reflect apoptotic cell death. This DMF-induced apoptosis was greater for CD8+vs CD4+, as well as for memory vs naive, and conventional vs regulatory T-cell subsets, a pattern which mirrored preferential T-cell subset losses that we observed during in vivo treatment of patients.
  
  
  CONCLUSIONS
  Differential apoptosis mediated by DMF may underlie the preferential lymphopenia of distinct T-cell subsets, including CD8+and memory T-cell subsets, seen in treated patients with MS. This differential susceptibility of distinct T-cell subsets to DMF-induced apoptosis may contribute to both the safety and efficacy profiles of DMF in patients with MS.
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Ghadiri
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Ayman
authors.initials: A
authors.lastname: Rezk
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Ashley
authors.initials: A
authors.lastname: Evans
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Giacomini
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.affiliation: Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or