Toxicity and therapeutic efficacy of high-dose interleukin 2. In vivo infusion of antibody to NK-1.1 attenuates toxicity without compromising efficacy against murine leukemia.
Toxicity and therapeutic efficacy of high-dose interleukin 2. In vivo infusion of antibody to NK-1.1 attenuates toxicity without compromising efficacy against murine leukemia.
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DOI：
10.1084/jem.169.1.161
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发表时间：
1989-01-01
影响因子：
15.3
通讯作者：
CHEEVER, MA
中科院分区：
文献类型：
--
作者：
PEACE, DJ;CHEEVER, MA
在目前的研究中，我们使用的治疗建立小鼠白血病，以确定淋巴细胞亚群负责毒性和高剂量IL-2的治疗效果。初步结果证实，高剂量IL-2诱导多种宿主细胞的显著增殖，包括NK细胞、Lyt-2+ T细胞、L3 T4 + T细胞和B细胞。输注抗NK-1.1抗体在体内耗尽NK-1.1+细胞，并大大降低IL-2的毒性，但不降低治疗效果。与此形成鲜明对比的是，宿主T细胞（Lyt-2+或L3 T4+）的耗竭对毒性没有影响，但大大降低了治疗效果。IL-2的疗效需要宿主T细胞，这证明了高剂量IL-2对已确定的恶性肿瘤的实质疗效可能需要存在的宿主抗肿瘤免疫力。由于已经显示对IL-2具有最实质性应答的人肿瘤（即，恶性黑色素瘤和肾细胞癌）是那些长期以来被认为在本地宿主中具有免疫原性的肿瘤，目前的研究预测，对于这些以及其它免疫原性人类肿瘤，应该可以通过选择性地消耗体内NK细胞来降低毒性，从而增加IL-2的治疗指数。
In the current study we used the therapy of established murine leukemia to identify the lymphocyte subsets responsible for toxicity and for therapeutic efficacy of high-dose IL-2. Initial results confirmed that high-dose IL-2 induces marked proliferation of a variety of host cells, including NK cells, Lyt-2+ T cells, L3T4+ T cells, and B cells. Infusion of antibody to NK-1.1 depleted NK-1.1+ cells in vivo and greatly reduced the toxicity of IL-2, but did not decrease therapeutic efficacy. By marked contrast, depletion of host T cells, either Lyt-2+ or L3T4+, had no effect on toxicity but greatly reduced therapeutic efficacy. The requirement for host T cells for the curative effect of IL-2 gives credence to the possibility that substantial efficacy of high-dose IL-2 against established malignancy may require existent host antitumor immunity. Since the human tumors that have been shown to have the most substantial responses to IL-2 (i.e., malignant melanoma and renal cell carcinoma) are those long considered to be immunogenic in the autochthonous host, the current study predicts that for these, as well as other immunogenic human tumors, it should be possible to decrease the toxicity and thus increase the therapeutic index of IL-2 by selectively depleting NK cells in vivo.
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DOI：
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发表时间：
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期刊：
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