Adult T cell leukemia: a potential target for ricin A chain immunotoxins.
Adult T cell leukemia: a potential target for ricin A chain immunotoxins.
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DOI：
10.1182/blood.v65.6.1416.bloodjournal6561416
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发表时间：
1985-06
期刊：
影响因子：
20.3
通讯作者：
M. Krönke;J. Depper;W. Leonard;E. Vitetta;T. Waldmann;W. Greene
中科院分区：
文献类型：
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作者：
M. Krönke;J. Depper;W. Leonard;E. Vitetta;T. Waldmann;W. Greene
成人T细胞白血病（ATL）是一种与人T细胞白血病/淋巴瘤病毒1型（HTLV-1）感染相关的几乎一致致命的成熟T细胞恶性肿瘤。这种白血病细胞的特点是表达大量的白细胞介素2 （IL-2）受体。为了制备一种对ATL细胞具有选择性细胞毒性的免疫毒素，我们将抗il -2受体单克隆抗体anti-Tac偶联到纯化的蓖麻毒素a链上。虽然未经修饰的抗tac对这些细胞的蛋白质合成没有影响，但抗tac -蓖麻毒素A链偶联物在2至6 × 10(-10) mol/L （ID50）浓度下对htlv -1感染的白血病T细胞系的蛋白质合成产生了一半的抑制作用。从两名ATL患者分离的白血病外周血T淋巴细胞获得了基本相同的ID50。相比之下，在htlv未感染、IL-2受体阴性的T和B细胞系中，蛋白质合成的半最大抑制需要200至1000倍的抗tac -蓖麻毒素A链偶联物浓度。未偶联的抗tac和免疫亲和纯化的IL-2均能完全抑制抗tac -蓖麻毒素A的毒性作用，证实了偶联物-IL-2受体相互作用的特异性。克隆实验表明，在浓度仅轻微影响IL-2受体阴性细胞的情况下，抗tac -蓖麻毒素A链能够消除超过99.9%的htlv -1感染的T细胞群。这些数据表明，抗tac -蓖麻毒素A在体外对htlv -1感染的白血病T细胞具有选择性细胞毒性，并提出了未来用免疫毒素特异性治疗干预这种疾病的可能性。
Adult T cell leukemia (ATL) is an almost uniformly fatal malignancy of mature T cells associated with human T cell leukemia/lymphoma virus type 1 (HTLV-1) infection. Cells from this leukemia are characterized by the expression of large numbers of receptors for interleukin 2 (IL-2). In an attempt to prepare an immunotoxin with selective cytotoxicity for ATL cells, we conjugated anti-Tac, a monoclonal anti-IL-2 receptor antibody, to purified ricin A chains. Although unmodified anti-Tac had no effect on the protein synthesis of these cells, anti-Tac-ricin A chain conjugates produced half-maximal inhibition of protein synthesis in HTLV-1-infected leukemic T cell lines at concentrations of 2 to 6 X 10(-10) mol/L (ID50). An essentially identical ID50 was obtained with leukemic peripheral blood T lymphocytes isolated from two patients with ATL. In contrast, half-maximal inhibition of protein synthesis in HTLV-uninfected, IL-2 receptor-negative T and B cell lines required 200- to 1,000-fold higher concentrations of anti-Tac-ricin A chain conjugates. Both unconjugated anti-Tac and immunoaffinity-purified IL-2 completely inhibited the toxic effects of anti-Tac-ricin A, confirming the specificity of the conjugate-IL-2 receptor interaction. Clonogenic assays demonstrated that anti-Tac-ricin A chain was able to eliminate greater than 99.9% of an HTLV-1-infected T cell population at concentrations only marginally affecting IL-2 receptor-negative cells. The data presented demonstrate that anti-Tac-ricin A is selectively cytotoxic for HTLV-1-infected leukemic T cells in vitro and raises the future possibility of specific therapeutic intervention with immunotoxins in this disease.