Disis M L, Bernhard H, Shiota F M, Hand S L, Gralow J R, Huseby E S, Gillis S, Cheever M A
Department of Medicine, University of Washington, Seattle 98195-6227, USA.
Blood. 1996 Jul 1;88(1):202-10.
The current studies evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. An important issue for developing vaccine therapy for human malignancy is identifying adjuvants that can elicit T-cell responses to proteins and peptides derived from "self" tumor antigens. GM-CSF, in vitro, stimulates the growth of antigen-presenting cells such as dendritic cells and macrophages. Initial experiments examined whether GM-CSF injected into the skin of rats could affect the number or character of antigen presenting cells, measured as class II major histocompatability complex expressing cells, in lymph nodes draining the injection site. Intradermal (id) inoculation of GM-CSF every 24 hours for a total of five inoculations resulted in an increase of class II+ fluorescing cells that peaked at the fourth inoculation. Subcutaneous (sq) inoculation resulted in an increase of class II+ fluorescing cells that peaked following the second inoculation, then decreased over time. Using this schema for "conditioning" the inoculation site, GM-CSF was administered id or sq for five injections and a foreign antigen, tetanus toxoid (tt), was given at the beginning or the end of the immunization cycle. Id immunization was more effective than sq at eliciting tt specific immunity. In addition, GM-CSF id, administered as a single dose with antigen, compared favorably with complete Freund's adjuvant (CFA) and alum in eliciting tt specific antibody and cellular immunity. We have shown that immunity to rat neu (c-erbB-2) protein, an oncogenic self protein, can be generated in rats by immunization with peptides derived from the normal rat neu sequence plus CFA. The current study demonstrates that rat neu peptides inoculated with GM-CSF could elicit a strong delayed type hypersensitivity reaction (DTH) response, whereas peptides alone were non-immunogenic. GM-CSF was as effective as CFA in generating rat neu specific DTH responses after immunization with a neu peptide based vaccine. Soluble GM-CSF is a potent adjuvant for the generation of immune responses to foreign proteins as well as peptides derived from a self tumor antigen.
目前的研究评估粒细胞巨噬细胞集落刺激因子（GM-CSF）作为一种疫苗佐剂。开发针对人类恶性肿瘤的疫苗疗法的一个重要问题是确定能够引发针对源自“自身”肿瘤抗原的蛋白质和肽的T细胞反应的佐剂。在体外，GM-CSF可刺激抗原呈递细胞如树突状细胞和巨噬细胞的生长。最初的实验研究了注射到大鼠皮肤中的GM-CSF是否会影响注射部位引流淋巴结中抗原呈递细胞的数量或特性，以表达II类主要组织相容性复合体的细胞来衡量。每24小时皮内（id）接种GM-CSF，共接种五次，导致II类+荧光细胞增加，在第四次接种时达到峰值。皮下（sq）接种导致II类+荧光细胞增加，在第二次接种后达到峰值，然后随时间下降。使用这种对接种部位进行“预处理”的方案，GM-CSF通过id或sq给药进行五次注射，并在免疫周期开始或结束时给予一种外来抗原破伤风类毒素（tt）。在引发tt特异性免疫方面，id免疫比sq更有效。此外，与抗原一起作为单剂量给药的GM-CSF id在引发tt特异性抗体和细胞免疫方面与完全弗氏佐剂（CFA）和明矾相比具有优势。我们已经表明，通过用源自正常大鼠neu序列的肽加CFA免疫，可以在大鼠中产生对致癌自身蛋白大鼠neu（c-erbB-2）蛋白的免疫。目前的研究表明，接种GM-CSF的大鼠neu肽可引发强烈的迟发型超敏反应（DTH），而单独的肽则无免疫原性。在用基于neu肽的疫苗免疫后，GM-CSF在产生大鼠neu特异性DTH反应方面与CFA一样有效。可溶性GM-CSF是产生针对外来蛋白质以及源自自身肿瘤抗原的肽的免疫反应的有效佐剂。
