title: Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro.
abstract: Alemtuzumab is a humanized monoclonal antibody specific for the CD52 protein present at high levels on the surface of B and T lymphocytes. In clinical trials, alemtuzumab has shown a clinical benefit superior to that of interferon-β in relapsing-remitting multiple sclerosis patients. Treatment with alemtuzumab leads to the depletion of circulating lymphocytes followed by a repopulation process characterized by alterations in the number, proportions and properties of lymphocyte subsets. Of particular interest, an increase in the percentage of T cells with a regulatory phenotype (Treg cells) has been observed in multiple sclerosis patients after alemtuzumab. Since Treg cells play an important role in the control of autoimmune responses, the effect of alemtuzumab on Treg cells was further studied in vitro. Alemtuzumab effectively mediated complement-dependent cytolysis of human T lymphocytes and the remaining population was enriched in T cells with a regulatory phenotype. The alemtuzumab-exposed T cells displayed functional regulatory characteristics including anergy to stimulation with allogeneic dendritic cells and ability to suppress the allogeneic response of autologous T cells. Consistent with the observed increase in Treg cell frequency, the CD25(hi) T-cell population was necessary for the suppressive activity of alemtuzumab-exposed T cells. The mechanism of this suppression was found to be dependent on both cell-cell contact and interleukin-2 consumption. These findings suggest that an alemtuzumab-mediated increase in the proportion of Treg cells may play a role in promoting the long-term efficacy of alemtuzumab in patients with multiple sclerosis.
authors.affiliation: Neuroimmunology Research, Genzyme, a Sanofi Company, Framingham, MA, USA.
authors.forename: Evis
authors.initials: E
authors.lastname: Havari
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Turner
authors.forename: Juanita
authors.initials: J
authors.lastname: Campos-Rivera
authors.forename: Srinivas
authors.initials: S
authors.lastname: Shankara
authors.forename: Tri-Hung
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Bruce
authors.initials: B
authors.lastname: Roberts
authors.forename: William
authors.initials: W
authors.lastname: Siders
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Kaplan
mesh_terms: D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000074301:CD52 Antigen; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; C508594:IL2 protein, human; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D000074323:Alemtuzumab
keywords: alemtuzumab; immune regulation; multiple sclerosis; regulatory T cells