Differential Effects of Denileukin Diftitox IL-2 Immunotoxin on NK and Regulatory T Cells in Nonhuman Primates
Differential Effects of Denileukin Diftitox IL-2 Immunotoxin on NK and Regulatory T Cells in Nonhuman Primates
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DOI：
10.4049/jimmunol.1200656
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发表时间：
2012-06-15
影响因子：
4.4
通讯作者：
Kawai, Tatsuo
中科院分区：
文献类型：
--
作者：
Yamada, Yohei;Aoyama, Akihiro;Kawai, Tatsuo
Denileukin diftitox （DD）是一种包含IL-2和白喉毒素的融合蛋白，最初期望通过选择性地消除显示高亲和力IL-2R （α - β - γ三聚体）的调节性T细胞（Tregs）来增强抗肿瘤免疫。虽然DD在灵长类动物中被证明会消耗一些Tregs，但它对NK细胞(CD16(+)CD8(+)NKG2A（+)CD3(-)）的影响仍然未知，NK细胞组成性地表达中等亲和力的IL-2R （β - γ二聚体），并在抗肿瘤免疫中发挥关键作用。为了解决这个问题，食蟹猴被静脉注射了两种剂量的DD（8或18 μ g/kg）。这种治疗导致可检测到的外周血静息treg (CD4(+)CD45RA（+)Foxp3(+)）的快速但短期的降低和激活treg (CD4(+)CD45RA（-)Foxp3（高））数量的短暂增加，随后它们的部分消耗（50-60%）。相反，所有NK细胞在给药后立即和持久地消失。与Tregs相比，这种差异不是由于NK细胞对DD的结合或内化程度更高。DD与IL-15（与IL-2R β - γ结合）共同给药，在体外和体内消除了DD诱导的NK细胞缺失，而不影响Treg的消除。综上所述，这些结果表明，DD对NK细胞具有强大的细胞毒作用，这种现象可能会损害其抗肿瘤特性。然而，IL-15与DD联合使用可以通过选择性地保护潜在的溶瘤性NK细胞来缓解这一问题，同时允许癌症患者消耗免疫抑制Tregs。免疫学杂志，2012,18(8):6063-6070。
Denileukin diftitox (DD), a fusion protein comprising IL-2 and diphtheria toxin, was initially expected to enhance antitumor immunity by selectively eliminating regulatory T cells (Tregs) displaying the high-affinity IL-2R (alpha-beta-gamma trimers). Although DD was shown to deplete some Tregs in primates, its effects on NK cells (CD16(+)CD8(+)NKG2A(+)CD3(-)), which constitutively express the intermediate-affinity IL-2R (beta-gamma dimers) and play a critical role in antitumor immunity, are still unknown. To address this question, cynomolgus monkeys were injected i.v. with two doses of DD (8 or 18 mu g/kg). This treatment resulted in a rapid, but short-term, reduction in detectable peripheral blood resting Tregs (CD4(+)CD45RA(+)Foxp3(+)) and a transient increase in the number of activated Tregs (CD4(+)CD45RA(-)Foxp3(high)), followed by their partial depletion (50-60%). In contrast, all NK cells were deleted immediately and durably after DD administration. This difference was not due to a higher binding or internalization of DD by NK cells compared with Tregs. Coadministration of DD with IL-15, which binds to IL-2R beta-gamma, abrogated DD-induced NK cell deletion in vitro and in vivo, whereas it did not affect Treg elimination. Taken together, these results show that DD exerts a potent cytotoxic effect on NK cells, a phenomenon that might impair its antitumoral properties. However, coadministration of IL-15 with DD could alleviate this problem by selectively protecting potentially oncolytic NK cells, while allowing the depletion of immunosuppressive Tregs in cancer patients. The Journal of Immunology, 2012, 188: 6063-6070.