Dasatinib inhibits recombinant viral antigen-specific murine CD4+ and CD8+ T-cell responses and NK-cell cytolytic activity in vitro and in vivo
Dasatinib inhibits recombinant viral antigen-specific murine CD4+ and CD8+ T-cell responses and NK-cell cytolytic activity in vitro and in vivo
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DOI：
10.1016/j.exphem.2008.09.013
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发表时间：
2009-02-01
影响因子：
2.6
通讯作者：
Hayball, John D.
中科院分区：
文献类型：
--
作者：
Fraser, Cara K.;Blake, Stephen J.;Hayball, John D.
Objective.达沙替尼（BMS-354825）是一种小分子Src/Abl酪氨酸激酶抑制剂，获批用于治疗慢性粒细胞白血病和费城染色体阳性急性淋巴细胞白血病。Src激酶家族的成员参与先天性和适应性免疫的诱导。本研究的目的是评估达沙替尼对抗原特异性CD 8（+）和CD 4（+）T细胞功能的抑制作用，以及对自然杀伤（NK）细胞的细胞毒性。为了评估达沙替尼介导的抗原特异性T细胞增殖抑制，使用了卵清蛋白特异性转基因CD 4（+）和CD 8（+）T细胞。用非复制型重组病毒免疫达沙替尼处理或对照小鼠后，测定内源性CD 4（+）和CD 8（+）T细胞应答。在接受达沙替尼治疗的小鼠中分析了RMA-S细胞（一种对NK细胞裂解敏感的主要组织相容性复合体（MHC）I类缺陷型胸腺瘤）的清除。达沙替尼在体外和体内抑制小鼠CD 4（+）和CD 8（+）转基因T细胞的抗原特异性增殖。内源性抗原特异性辅助性T细胞回忆反应和诱导T细胞介导的细胞毒性免疫接种后的非复制重组病毒也被抑制。因此，在体内NK细胞清除MHC I类缺陷细胞的能力。这些发现表明，达沙替尼具有在临床剂量下调节宿主免疫应答的潜力，并突出了脱靶应用的范围，例如，在自身免疫发病机制和同种异体组织移植的背景下的治疗性免疫抑制。(C)2009 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Objective. Dasatinib (BMS-354825) is a small molecule Src/Abl tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Members of the Src family of kinases are involved in the induction of innate and adaptive immunity. The purpose of this study was to evaluate the inhibitory action of dasatinib on antigen-specific CD8(+) and CD4(+) T-cell function, its well as natural killer (NK) cell cytotoxicity.Materials and Methods. To assess dasatinib-mediated inhibition of antigen-specific T-cell proliferation, transgenic CD4(+) and CD8(+) T cells specific for ovalbumin were utilized. Endogenous CD4(+) and CD8(+) T-cell responses were determined following immunization of dasatinib-treated or control mice with a nonreplicating recombinant virus. Clearance of the RMA-S cells, a major histocompatibility complex (MHC) class I-deficient thymoma sensitive to NK-cell lysis, was analyzed in mice undergoing dasatinib treatment.Results. Dasatinib inhibited antigen-specific proliferation of murine CD4(+) and CD8(+) transgenic T cells in vitro and in vivo. Endogenous antigen-specific helper T-cell recall responses and induction of T-cell-mediated cytotoxicity following immunization with a nonreplicating recombinant virus were also inhibited. So to wits the ability of NK cells to eliminate MHC class I-deficient cells in vivo.Conclusions. These findings suggest that dasatinib has the potential to modulate the host immune response at clinical doses and highlights scope for off target applications, e.g., therapeutic immunosuppression in the context of autoimmune pathogenesis and allogeneic tissue transplantation. (C) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.