Therapeutic potential of a tumor-specific, MHC-unrestricted T-cell receptor expressed on effector cells of the innate and the adaptive immune system through bone marrow transduction and immune reconstitution
Therapeutic potential of a tumor-specific, MHC-unrestricted T-cell receptor expressed on effector cells of the innate and the adaptive immune system through bone marrow transduction and immune reconstitution
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DOI：
10.1182/blood-2004-10-3848
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发表时间：
2005-06-15
期刊：
影响因子：
20.3
通讯作者：
Finn, OJ
中科院分区：
文献类型：
--
作者：
Alajez, NM;Schmielau, J;Finn, OJ
从肿瘤抗原MUC1特异性的人t细胞克隆中分离到具有独特的主要组织相容性复合体（MHC）无限制抗原结合特性的t细胞受体（TCR）。该TCR将其表位结合在MUC1蛋白上，无需加工和呈递。单链V α / V β /C β (scTCR)与CD3 zeta （zeta）链融合，允许在先天（粒细胞、巨噬细胞、自然杀伤[NK]细胞）和适应性（T细胞和B细胞）免疫系统的细胞表面表达。为了测试先天免疫系统细胞在提供肿瘤抗原特异性TCR时对肿瘤的排斥能力，我们用编码该受体的逆转录病毒载体转导骨髓细胞重组了严重联合免疫缺陷（SCID）小鼠，并用muc1阳性的人类肿瘤攻击它们。这些小鼠对肿瘤生长的控制明显优于对照组小鼠。我们在转人MUC1基因的免疫活性小鼠中进行了类似的实验。TCR在大比例细胞上的表达不会导致表达MUC1的组织浸润或破坏。重组小鼠能控制转染muc1的肿瘤的生长，但不能控制亲代对照肿瘤的生长。scTCR的表达似乎是终身的，表明自我更新干细胞的成功转导。(c) 2005年由美国血液学会出版。
T-cell receptor (TCR) with unique major histocompatibility complex (MHC)-unrestricted antigen-binding properties was isolated from a human T-cell clone specific for the tumor antigen MUC1. This TCR binds its epitope on the MUC1 protein without the requirement of processing and presentation. A single-chain V alpha/ V beta/C beta (scTCR) was fused to a CD3 zeta (zeta) chain to allow expression on the surface of cells of the innate (granulocytes, macrophages, natural killer [NK] cells) as well as the adaptive (T and B cells) immune system. To test the ability of the cells of the innate immune system to reject a tumor when provided with a tumor antigen-specific TCR, we reconstituted severe combined immunodeficiency (SCID) mice with bone marrow cells transduced with a retroviral vector encoding this receptor and challenged them with a MUC1-positive human tumor. These mice controlled the growth of the tumor significantly better than the control mice. We performed a similar experiment in immunocompetent mice transgenic for human MUC1. Expression of the TCR on large percentages of cells did not result in infiltration or destruction of tissues expressing MUC1. Reconstituted mice controlled the outgrowth of a MUC1-transfected but not the parental control tumor. scTCR expression appears lifelong, suggesting a successful transduction of the self-renewing stem cells. (c) 2005 by The American Society of Hematology.