title: Enhancement of anti-STLV-1/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia and inflammatory diseases. Because anti-HTLV-1 immune responses are critical for suppressing infected cells, enhancing cellular immunity is beneficial for the treatment of HTLV-1-associated diseases. Using simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaques, we analyzed the immune responses to viral antigens and the dynamics of virus-infected cells. The chemokine receptor CCR4 is expressed on STLV-1 infected cells, and administration of humanized monoclonal antibody to CCR4, mogamulizumab, dramatically decreased the number of STLV-1-infected cells in vivo. Concurrently, mogamulizumab treatment enhanced STLV-1 specific CD4(+) and CD8(+) T cell responses by simultaneously targeting CCR4(+) effector regulatory T (Treg) cells and infected cells. Mogamulizumab promoted the phagocytosis of CCR4(+) infected cells by macrophages, which likely enhanced antigen presentation. Vaccination with recombinant vaccinia virus (rVV) expressing viral antigens suppressed the proviral load and the number of Tax-expressing cells. Enhanced T-cell responses were also observed in some ATL patients who were treated with mogamulizumab. This study shows that mogamulizumab works not only by killing CCR4(+) infected cells directly, but also by enhancing T cell responses by increasing the phagocytosis of infected cells by antigen-presenting cells and suppressing CCR4(+) effector Treg cells.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.|Japan Society for the Promotion of Science (JSPS), Chiyoda-ku, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugata
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Jun-Ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Michi
authors.initials: M
authors.lastname: Miura
authors.affiliation: Laboratory of Evolutional Virology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akari
authors.affiliation: Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan.
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.affiliation: Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Kisato
authors.initials: K
authors.lastname: Nosaka
authors.affiliation: Department of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzushima
authors.affiliation: Department of Hematology, Osaka General Hospital of West Japan Railway Company, Osaka, Japan.
authors.forename: Ki-Ryang
authors.initials: KR
authors.lastname: Koh
authors.affiliation: North Medical Center, Kyoto Prefectural University of Medicine, Yosano-cho, Kyoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000494:pharmacology; D000956:Antigens, Viral / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006800:Deltaretrovirus Infections / Q000188:drug therapy* / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008251:Macaca / Q000276:immunology / Q000821:virology; D051379:Mice; D054398:Receptors, CCR4 / Q000378:metabolism*; D015303:Simian T-lymphotropic virus 1 / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000956:Antigens, Viral; D054398:Receptors, CCR4; C549035:mogamulizumab