IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity
IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity
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DOI：
10.1182/blood-2007-06-094615
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发表时间：
2007-11-01
期刊：
影响因子：
20.3
通讯作者：
Palena, Claudia
中科院分区：
文献类型：
--
作者：
Litzinger, Mary T.;Fernando, Romaine;Palena, Claudia
CD 4（+）CD 25（+）Foxp 3（+）调节性T（Treg）细胞与缺乏有效的抗肿瘤免疫有关。白介素2（IL-2）和白喉毒素的融合蛋白Denileukin diftitox（DAB（389）IL-2）提供了靶向Treg细胞的手段。在这项研究中，我们检查了（1）地尼白介素diftitox对各种淋巴区室中Treg细胞缺失的影响，以及（2）地尼白介素diftitox与重组痘病毒疫苗组合以增强抗原特异性免疫应答的剂量安排。正常C57 BL/6小鼠的脾脏、外周血和骨髓中的Treg细胞在单次腹膜内注射地尼白介素diftitox后不同程度地减少;减少在24小时内明显，持续约10天。在接种疫苗前一天注射地尼白介素diftitox增强了抗原特异性T细胞应答，高于单独接种疫苗诱导的水平。这些研究首次在鼠模型中显示（1）地尼白介素diftitox对不同细胞区室中的Treg细胞的不同作用，（2）地尼白介素diftitox与疫苗组合以增强抗原特异性T细胞免疫应答的优点，（3）地尼白介素diftitox对针对活病毒载体的宿主免疫应答缺乏抑制，和（4）当与疫苗联合使用时，地尼白介素diftitox的剂量安排的重要性。
CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells have been implicated in the lack of effective antitumor immunity. Denileukin diftitox (DAB(389)IL-2), a fusion protein of interleukin 2 (IL-2) and diphtheria toxin, provides a means of targeting Treg cells. In this study, we examined (1) the effect of denileukin diftitox on the deletion of Treg cells in various lymphoid compartments and (2) the dose scheduling of denileukin diftitox in combination with a recombinant poxviral vaccine to enhance antigenspecific immune responses. Treg cells in spleen, peripheral blood, and bone marrow of normal C57BL/6 mice were variously reduced after a single intraperitoneal injection of denileukin diftitox; the reduction was evident within 24 hours and lasted approximately 10 days. Injection of denileukin diftitox I day before vaccination enhanced antigen-specific T-cell responses above levels induced by vaccination alone. These studies show for the first time in a murine model (1) the differential effects of denileukin diftitox on Treg cells in different cellular compartments, (2) the advantage of combining denileukin diftitox with a vaccine to enhance antigen-specific T-cell immune responses, (3) the lack of inhibition by denileukin diftitox of host immune responses directed against a live viral vector, and (4) the importance of dose scheduling of denileukin diftitox when used in combination with a vaccine.