title: Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis.
abstract: Alemtuzumab (anti-CD52 mAb) provides long-lasting disease activity suppression in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion. The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial, which was recently completed and led to the submission of alemtuzumab for U.S. Food and Drug Administration approval as a treatment for RRMS. Alemtuzumab-treated patients exhibited a nearly complete depletion of circulating CD4(+) lymphocytes at day 7. During the immunological reconstitution, CD4(+)CD25(+)CD127(low) regulatory T cells preferentially expanded within the CD4(+) lymphocytes, reaching their peak expansion at month 1. The increase in the percentage of TGF-β1-, IL-10-, and IL-4-producing CD4(+) cells reached a maximum at month 3, whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline. A gradual increase in serum IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment. In vitro studies have demonstrated that IL-7 induced an expansion of CD4(+)CD25(+)CD127(low) regulatory T cells and a decrease in the percentages of Th17 and Th1 cells. In conclusion, our results indicate that differential reconstitution of T cell subsets and selectively delayed CD4(+) T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity.
authors.affiliation: Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Yazhong
authors.initials: Y
authors.lastname: Tao
authors.forename: Manisha
authors.initials: M
authors.lastname: Chopra
authors.forename: Mihye
authors.initials: M
authors.lastname: Ahn
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marcus
authors.forename: Neelima
authors.initials: N
authors.lastname: Choudhary
authors.forename: Hongtu
authors.initials: H
authors.lastname: Zhu
authors.forename: Silva
authors.initials: S
authors.lastname: Markovic-Plese
mesh_terms: D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000951:Antigens, Neoplasm / Q000276:immunology*; D000074301:CD52 Antigen; D002478:Cells, Cultured; D017326:Clinical Trials, Phase III as Topic; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000494:pharmacology / Q000627:therapeutic use; D015851:Interleukin-7 / Q000494:pharmacology; D008212:Lymphocyte Depletion / Q000379:methods*; D008222:Lymphokines / Q000097:blood / Q000378:metabolism; D008231:Lymphopenia / Q000097:blood / Q000139:chemically induced / Q000276:immunology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D018417:Th1 Cells / Q000473:pathology; D058504:Th17 Cells / Q000473:pathology; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D015851:Interleukin-7; D008222:Lymphokines; D000074323:Alemtuzumab; D016899:Interferon-beta; D000068556:Interferon beta-1a