Delivery of IL-12 intranasally leads to reduced IL-12-mediated toxicity
Delivery of IL-12 intranasally leads to reduced IL-12-mediated toxicity
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DOI：
10.1016/s1567-5769(02)00233-3
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发表时间：
2003-06-01
影响因子：
5.6
通讯作者：
Metzger, DW
中科院分区：
文献类型：
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作者：
Huber, VC;Arulanandam, BP;Metzger, DW
白介素12(IL-12)是一种异二聚体细胞因子，能增强对细菌、寄生虫和病毒病原体的免疫反应，并在动物模型中导致肿瘤消退。出于这个原因，正在研究将IL-12用作疫苗佐剂和癌症治疗的治疗剂。不幸的是，在临床试验中观察到的这种分子的极端毒性限制了它的使用。这种毒性与增加干扰素-γ的表达、降低血糖水平以及改变脾和十二指肠的组织学反应有关。在本研究中，我们发现鼻腔(I.N.)与通常使用的皮下接种相比，IL-12的接种是一种毒性较低的接种途径。注射给药时，IL-12诱导的全身干扰素-γ的产生较少，病理组织改变较少，但有效，如CD3+T细胞激活和Th1相关免疫球蛋白(即血清IgG2a)的产生增加。因此，IL-12可以通过I.N.安全有效地输送。这一发现可能会使IL-12发挥其临床潜力。(C)2002 Elsevier Science B.V.保留所有权利。
Interleukin-12 (IL-12) is a heterodimeric cytokine that enhances immune responses to bacterial, parasitic, and viral pathogens, and leads to tumor regression in animal models. For this reason, the use of IL-12 as a vaccine adjuvant and as a therapeutic agent for the treatment of cancer is being investigated. Unfortunately, the extreme toxicity of this molecule observed during clinical trials has limited its use. This toxicity correlates with increased IFN-gamma expression, decreased glucose levels, and altered histological responses in the spleen and duodenum. In this study, we show that intranasal (i.n.) delivery of IL-12 is a less toxic route of inoculation compared to the commonly employed subcutaneous route. When delivered i.n., IL-12 induces less systemic IFN-gamma production and fewer pathological tissue changes, yet is efficacious, as indicated by enhanced CD3+ T cell activation and increased production of Th1-associated immunoglobulins (i.e., serum IgG2a). Thus, IL-12 can be delivered safely and effectively by the i.n. route, a finding which may allow IL-12 to fulfill its clinical potential. (C) 2002 Elsevier Science B.V. All rights reserved.