title: Immunological studies of mitoxantrone in primary progressive MS.
abstract: Mitoxantrone (MX) has demonstrated efficacy in multiple sclerosis (MS), but its immunologic mechanisms of action are poorly understood. Furthermore, no study has examined the immunological effects of MX in primary progressive MS (PPMS). This study investigated the immunological effects of MX therapy in PPMS patients. Lymphocyte phenotypes and chemokine receptor (CCR) expression were evaluated by flow cytometry on fresh PBMC from 20 PPMS patients enrolled in a placebo (PLC)-controlled trial of MX. Longitudinal data were collected at weeks 0, 12, 24, 36 and short-term data (pre-/post-infusion) were collected at weeks 0 and 36. CXCR3, CCR1, CCR2 and CCR5 on CD4 and CD8 T cells and CD14 monocytes were evaluated. MX therapy induced a significant increase in the proportion of CD8 T cells (CD45RO(-)) over 9 months. Expression of several CCR increased following MX treatment. Two of the eight MX-treated patients demonstrated dramatic upregulation (70-76%) of CCR2 on monocytes. These two patients were the only MX-treated patients to demonstrate active inflammation by magnetic resonance imaging (MRI). PLC patients did not show significant changes in CCR expression. MX therapy was not associated with selective loss of CD4, CD8 or CD14 cells 1 month after treatment or over 9 months. These results suggest that MX therapy leads to a longitudinal increase in CD8 T cells and may increase CCR in patients with inflammation on MRI. Overall, MX did not show extensive immune changes in PPMS, although patients with active disease (gadolinium enhancing lesions) may identify a subset of PPMS subjects who respond immunologically to MX therapy. An improved understanding of MX may help identify markers of disease activity and response to therapy.
authors.affiliation: Department of Neurosciences NC30, Lerner Research Institute, Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, OH, USA. pelfrec@ccf.org
authors.forename: Clara M
authors.initials: CM
authors.lastname: Pelfrey
authors.forename: Anne C
authors.initials: AC
authors.lastname: Cotleur
authors.forename: Natacha
authors.initials: N
authors.lastname: Zamor
authors.forename: Jar-Chi
authors.initials: JC
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
mesh_terms: D000328:Adult; D016516:CD4-CD8 Ratio; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use*; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy* / Q000276:immunology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology
chemical_list: C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D008942:Mitoxantrone; D017493:Leukocyte Common Antigens