title: Mogamulizumab, an anti-CCR4 antibody, targets human T-lymphotropic virus type 1-infected CD8+ and CD4+ T cells to treat associated myelopathy.
abstract: BACKGROUND
  Human T-lymphotropic virus type 1 (HTLV-1) can cause chronic spinal cord inflammation, known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since CD4(+)CCR4(+) T cells are the main HTLV-1 reservoir, we evaluated the defucosylated humanized anti-CCR4 antibody mogamulizumab as a treatment for HAM/TSP.
  
  
  METHODS
  We assessed the effects of mogamulizumab on peripheral blood mononuclear cells from 11 patients with HAM/TSP. We also studied how CD8(+) T cells, namely CD8(+) CCR4(+) T cells and cytotoxic T lymphocytes, are involved in HTLV-1 infection and HAM/TSP pathogenesis and how they would be affected by mogamulizumab.
  
  
  RESULTS
  Mogamulizumab effectively reduced the HTLV-1 proviral load (56.4% mean reduction at a minimum effective concentration of 0.01 µg/mL), spontaneous proliferation, and production of proinflammatory cytokines, including interferon γ (IFN-γ). Like CD4(+)CCR4(+) T cells, CD8(+)CCR4(+) T cells from patients with HAM/TSP exhibited high proviral loads and spontaneous IFN-γ production, unlike their CCR4(-) counterparts. CD8(+)CCR4(+) T cells from patients with HAM/TSP contained more IFN-γ-expressing cells and fewer interleukin 4-expressing cells than those from healthy donors. Notably, Tax-specific cytotoxic T lymphocytes that may help control the HTLV-1 infection were overwhelmingly CCR4(-).
  
  
  CONCLUSIONS
  We determined that CD8(+)CCR4(+) T cells and CD4(+)CCR4(+) T cells are prime therapeutic targets for treating HAM/TSP and propose mogamulizumab as a new treatment.
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science Division of Nephrology and Hypertension.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Ariella
authors.initials: A
authors.lastname: Coler-Reilly
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Araya
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yagishita
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kunitomo
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Shibagaki
authors.affiliation: Institute of Medical Science, Tokyo Medical University.
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.affiliation: Institute of Medical Science, Tokyo Medical University.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan.
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic / Q000628:therapy*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C515354:CCR4 protein, human; D054398:Receptors, CCR4; C549035:mogamulizumab
keywords: CCR4; CD8; HAM/TSP; HTLV-1; mogamulizumab