Partial Reduction of Human FOXP3+ CD4 T Cells In Vivo After CD25-directed Recombinant Immunotoxin Administration
Partial Reduction of Human FOXP3+ CD4 T Cells In Vivo After CD25-directed Recombinant Immunotoxin Administration
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DOI：
10.1097/cji.0b013e31815dc0e8
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发表时间：
2008-02
影响因子：
3.9
通讯作者：
D. Powell;Peter Attia;V. Ghetie;J. Schindler;E. Vitetta;S. Rosenberg
中科院分区：
文献类型：
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作者：
D. Powell;Peter Attia;V. Ghetie;J. Schindler;E. Vitetta;S. Rosenberg
对自身蛋白的耐受性的调节和T细胞应答的抑制部分归因于CD 25 + CD 4 + T调节（Treg）细胞的活性。此外，Treg细胞可以抑制临床前模型中过继免疫疗法和主动免疫方法的抗肿瘤有效性。为了从人外周血单核细胞中选择性消除Treg细胞以潜在地支持抗肿瘤应答，我们评估了CD 25定向免疫毒素RFT 5-SMPT-dgA的Treg细胞消耗能力。在临床前研究中，人外周血单核细胞与RFT 5-SMPT-dgA的孵育在体外介导了表达CD 25+、Foxp 3的CD 4 + T细胞水平的部分降低。6例转移性黑色素瘤患者接受RFT 5-SMPT-dgA给药后，体内CD 25 high CD 4 + T细胞数量出现短暂但稳健的减少（最低值时平均减少97.5%;从69.4±12.4个细胞/μL降至1.7±0.3个细胞/μL）。FOXP 3 + CD 4 + T细胞数量的减少不太全面（最低值时平均减少71.3%;从66.6±16.5个细胞/μL降至14.2±3.9个细胞/μL）。这导致体内稳定数量的CD 25低/阴性FOXP 3 + CD 4 + T细胞的选择性持久性。在任何患者中均未观察到客观抗肿瘤缓解。我们的研究结果表明，CD 25导向的RFT 5-SMPT-dgA免疫毒素可以介导体外和体内Treg细胞频率和数量的短暂、部分减少，并表明体内人Treg细胞的全面根除可能需要靶向和消除表达高水平和低水平CD 25的FOXP 3 + CD 4 + T细胞的能力。
The regulation of tolerance to self-proteins and the suppression of T-cell responses have in part been attributed to the activity of CD25+CD4+ T regulatory (Treg) cells. Further, Treg cells can inhibit the antitumor effectiveness of adoptive immunotherapy and active immunization approaches in preclinical models. In an effort to selectively eliminate Treg cells from human peripheral blood mononuclear cell to potentially bolster antitumor responses, we have evaluated the Treg-cell depleting capacity of the CD25-directed immunotoxin, RFT5-SMPT-dgA. In preclinical studies, incubation of human peripheral blood mononuclear cell with RFT5-SMPT-dgA mediated a partial reduction in the levels of CD25+, Foxp3-expressing CD4+ T cells in vitro. Administration of RFT5-SMPT-dgA to 6 patients with metastatic melanoma induced a transient but robust reduction in the number of CD25high CD4+ T cells in vivo (a 97.5% mean reduction at nadir; from 69.4±12.4 cells/μL to 1.7±0.3 cells/μL). The reduction in FOXP3+ CD4+ T-cell number was less comprehensive (a 71.3% mean reduction at nadir; from 66.6±16.5 cells/μL to 14.2±3.9 cells/μL). This resulted in the selective persistence of a stable number of CD25low/neg FOXP3+ CD4+ T cells in vivo. No objective antitumor responses were seen in any patient. Our results indicate that the CD25-directed, RFT5-SMPT-dgA immunotoxin can mediate a transient, partial reduction in Treg-cell frequency and number in vitro and in vivo and suggest that comprehensive eradication of human Treg cells in vivo may require the ability to target and eliminate FOXP3+ CD4+ T cells expressing both high and low levels of CD25.