Comparative methodologies of regulatory T cell depletion in a murine melanoma model
Comparative methodologies of regulatory T cell depletion in a murine melanoma model
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DOI：
10.1016/j.jim.2008.01.012
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发表时间：
2008-04-20
影响因子：
2.2
通讯作者：
Riker, Adam I.
中科院分区：
文献类型：
--
作者：
Matsushita, Norimasa;Pilon-Thomas, Shari A.;Riker, Adam I.
最近人们对调节性T细胞（Tcells）的耗竭产生了兴趣，这是黑色素瘤患者免疫治疗的多方面方法的一部分。这在一定程度上是由于最近的研究结果令人信服地表明，TGFAP是调节甚至抑制对生长的肿瘤细胞的免疫反应的组成部分。因此，我们比较了三种Treg消耗和/或消除的方法，利用低剂量环磷酰胺（CY），一种针对在T细胞上发现的IL-2受体（PC 61）的特异性抗体，以及使用地尼白介素diftitox（1313），其是一种融合蛋白，被设计成对表达IL-2受体的细胞具有直接杀细胞作用。我们表明，CY管理导致三种试剂中TdR的最高降低。然而，CY引起的T淋巴细胞减少也与CD 8（+）T细胞减少和缺乏肿瘤抗原引发有关。DD的利用导致> 50%的Treg细胞减少，而对其他T细胞亚群没有平行的杀细胞作用，但不增强针对B 16黑素瘤的抗肿瘤免疫力。最后，PC61显示TcR的中度降低，持续时间长于其他试剂，而CD 8（+）T细胞总数没有减少。此外，PC61治疗没有消除树突状细胞（DC）引起的肿瘤抗原特异性免疫。因此，我们得出结论，除了与基于DC的免疫疗法组合时提供协同效应的证据外，PC61给药是降低鼠黑色素瘤模型中的TcR的最有效方法。(C)2008 Elsevier B. V.保留所有权利。
There has been recent interest in the depletion of regulatory T cells (Tregs) as part of a multi-faceted approach to the immunotherapy of melanoma patients. This is in part due recent findings that convincingly show that Tregs are an integral part of regulating and even suppressing an immune response to growing tumor cells. We therefore compared three methods of Treg depletion and/or elimination, utilizing low dose cyclophosphamide (CY), a specific antibody directed against the IL-2 receptor found on Tregs (PC61) and the use of denileukin diftitox (1313), which is a fusion protein designed to have a direct cytocidal action on cells which express the IL-2 receptor. We show that CY administration resulted in the highest reduction in Tregs among the three reagents. However, the reduction in Tregs with CY was also associated with the concomitant reduction of CD8(+) T cells and a lack of tumor antigen priming. Utilization of DD resulted in a > 50% Treg cell reduction without parallel cytocidal effects upon other T cell subsets but did not enhance anti-tumor immunity against B 16 melanoma. Lastly, the PC61 showed a moderate reduction of Tregs that lasted longer than the other reagents, without a reduction in the total number of CD8(+) T cells. Furthermore, PC61 treatment did not abrogate tumor antigen-specific immunity elicited by dendritic cells (DC). We therefore conclude that PC61 administration was the most effective method of reducing Tregs in a murine melanoma model in addition to providing evidence of a synergistic effect when combined with DC-based immunotherapy. (C) 2008 Elsevier B.V. All rights reserved.