2. Academic Validation
  3. Mogamulizumab, an anti-CCR4 antibody, targets human T-lymphotropic virus type 1-infected CD8+ and CD4+ T cells to treat associated myelopathy

Mogamulizumab, an anti-CCR4 antibody, targets human T-lymphotropic virus type 1-infected CD8+ and CD4+ T cells to treat associated myelopathy

  • J Infect Dis. 2015 Jan 15;211(2):238-48. doi: 10.1093/infdis/jiu438.
Junji Yamauchi 1,  Ariella Coler-Reilly 2,  Tomoo Sato 2,  Natsumi Araya 2,  Naoko Yagishita 2,  Hitoshi Ando 2,  Yasuo Kunitomo 2,  Katsunori Takahashi 2,  Yuetsu Tanaka 3,  Yugo Shibagaki 4,  Kusuki Nishioka 5,  Toshihiro Nakajima 5,  Yasuhiro Hasegawa 6,  Atae Utsunomiya 7,  Kenjiro Kimura 4,  Yoshihisa Yamano 2
Affiliations

Affiliations

  • 1 Department of Rare Diseases Research, Institute of Medical Science Division of Nephrology and Hypertension.
  • 2 Department of Rare Diseases Research, Institute of Medical Science.
  • 3 Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa.
  • 4 Division of Nephrology and Hypertension.
  • 5 Institute of Medical Science, Tokyo Medical University.
  • 6 Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki.
  • 7 Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan.
PMID: 25104771 DOI: 10.1093/infdis/jiu438
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.

Keywords

CCR4; CD8; HAM/TSP; HTLV-1; mogamulizumab.

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