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.
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Mogamulizumab 是一种抗 CCR4 抗体，针对人类 T 淋巴细胞病毒 1 型感染的 CD8 和 CD4 T 细胞来治疗相关的脊髓病。
DOI：
10.1093/infdis/jiu438
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Yamano Y.
中科院分区：
文献类型：
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作者：
Yamauchi J;Coler-Reilly A;Sato T;Araya N;Yagishita N;Ando H;Kunitomo Y;Takahashi K;Tanaka Y;Shibagaki Y;Nishioka K;Nakajima T;Hasegawa Y;Utsunomiya A;Kimura K;Yamano Y.
人类嗜T淋巴细胞病毒1型（humanT-lymphotropicvirustype 1，HTLV-1）可引起慢性脊髓炎症，即HTLV-1相关性脊髓病/热带痉挛性截瘫（HTLV-1-associatedmyelopathy/tropicalspasticparaparesis，HAM/TSP）。由于CD 4 + CCR 4 +T细胞是主要的HTLV-1水库，我们评估了去岩藻糖基化的人源化的抗CCR 4抗体mogamulizumab作为HAM/TSP.MethodsWe治疗评估mogamulizumab对11例HAM/TSP患者外周血单核细胞的影响。我们还研究了CD 8 +T细胞（即CD 8 + CCR 4 +T细胞和细胞毒性T淋巴细胞）如何参与HTLV-1感染和HAM/TSP发病机制以及它们如何受到mogamulizumab的影响。（最低有效浓度为0.01 µg/mL时平均减少56.4%）、自发增殖和促炎细胞因子的产生，包括干扰素γ（IFN-γ）。与CD 4 + CCR 4 +T细胞一样，来自HAM/TSP患者的CD 8 + CCR 4 +T细胞表现出高前病毒载量和自发IFN-γ产生，与CCR 4 −对应物不同。与健康供体相比，HAM/TSP患者的CD 8 + CCR 4 +T细胞含有更多的表达IFN-γ的细胞和更少的表达白细胞介素4的细胞。值得注意的是，Tax特异性细胞毒性T淋巴细胞，可能有助于控制HTLV-1感染压倒性CCR 4-.ConclusionsWe确定，CD 8 + CCR 4 +T细胞和CD 4 + CCR 4 +T细胞是治疗HAM/TSP的主要治疗靶点，并提出mogamulizumab作为一种新的治疗方法。
BackgroundHuman 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.MethodsWe 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.ResultsMogamulizumab 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−.ConclusionsWe 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.