Safety and immunologic effects of IL-15 administration in nonhuman primates
Safety and immunologic effects of IL-15 administration in nonhuman primates
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DOI：
10.1182/blood-2008-12-189266
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发表时间：
2009-09-17
期刊：
影响因子：
20.3
通讯作者：
Riddell, Stanley R.
中科院分区：
文献类型：
--
作者：
Berger, Carolina;Berger, Michael;Riddell, Stanley R.
调节内源性或转移的T细胞免疫的细胞因子的施用可以改善目前的临床免疫治疗方法。白细胞介素-2（IL-2）最常用于此目的，但会引起全身毒性，并优先驱动CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞的扩增，这可抑制抗肿瘤免疫。IL-15属于γ c细胞因子家族，具有与IL-2相似的性质，包括诱导T细胞增殖的能力。尽管IL-2促进细胞凋亡并限制CD 8（+）记忆T细胞的存活，但IL-15是建立和维持CD 8（+）T细胞记忆所必需的。然而，有限的数据可用于指导IL-15的临床使用。在这里，我们证明了在非人灵长类动物中，IL-15给药扩增了外周血中的记忆性CD 8（+）和CD 4（+）T细胞以及自然杀伤（NK）细胞，而CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞的增加最小。每天给予IL-15导致血浆IL-15水平持续升高和一过性毒性。IL-15的间歇给药允许在剂量之间清除IL-15，并且安全超过3周。这些发现表明，IL-15具有与IL-2所描述的免疫调节特性不同的深刻的免疫调节特性，并表明在临床研究中应考虑间歇施用IL-15。（血。2009; 114：2417-2426）
The administration of cytokines that modulate endogenous or transferred T-cell immunity could improve current approaches to clinical immunotherapy. Interleukin-2 (IL-2) is used most commonly for this purpose, but causes systemic toxicity and preferentially drives the expansion of CD4(+)CD25(+)Foxp3(+) regulatory T cells, which can inhibit antitumor immunity. IL-15 belongs to the gamma c cytokine family and possesses similar properties to IL-2, including the ability to induce T-cell proliferation. Whereas IL-2 promotes apoptosis and limits the survival of CD8(+) memory T cells, IL-15 is required for the establishment and maintenance of CD8(+) T-cell memory. However, limited data are available to guide the clinical use of IL-15. Here, we demonstrate in nonhuman primates that IL-15 administration expands memory CD8(+) and CD4(+) T cells, and natural killer (NK) cells in the peripheral blood, with minimal increases in CD4(+)CD25(+)Foxp3(+) regulatory T cells. Daily administration of IL-15 resulted in persistently elevated plasma IL-15 levels and transient toxicity. Intermittent administration of IL-15 allowed clearance of IL-15 between doses and was safe for more than 3 weeks. These findings demonstrate that IL-15 has profound immunomodulatory properties distinct from those described for IL-2, and suggest that intermittent administration of IL-15 should be considered in clinical studies. (Blood. 2009; 114: 2417-2426)