Exploiting dendritic cells to improve vaccine efficacy.
Exploiting dendritic cells to improve vaccine efficacy.
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DOI：
10.1172/jci15962
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发表时间：
2002-06
期刊：
影响因子：
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通讯作者：
R. Steinman;M. Pope
中科院分区：
文献类型：
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作者：
R. Steinman;M. Pope
艾滋病疫苗的现状使疫苗生物学所面临的挑战更加突出（见Letvin，本透视系列，参考文献1）。多年来，关于HIV-1基因组及其蛋白质以及免疫系统识别的许多抗原的数据已经存在。尽管如此，这些信息还没有容易地转化为候选疫苗，诱导广泛和持久的T细胞介导的免疫，被认为是必要的，以保护人们免受艾滋病（2 - 5）。疫苗也缺乏许多其他严重的感染，其中T细胞介导的免疫应该是保护性的。这些病原体包括其基因组序列和抗原蛋白被充分表征的病原体：结核病、疟疾、单纯疱疹病毒、乳头状瘤、EB病毒和丙型肝炎病毒。本质上，外来抗原的鉴定是必要的，但不足以生产在T细胞球中有效的疫苗。需要更好的疫苗递送和疫苗佐剂或免疫增强剂（6，7）。我们建议，在应对未来疫苗生物学的每一个挑战时，应考虑和利用树突状细胞（DC）生理学（见表1）。树突状细胞作为天然佐剂调节抗原特异性免疫。作为抗原呈递细胞，DC捕获抗原，将其加工成肽，并将其在MHC的产物上呈递给T细胞。树突状细胞在抗原呈递方面既高效又专业化，并且它们控制随后的免疫应答的幅度、质量和记忆。DC已成功用作小鼠中的细胞佐剂，以引发针对病原体和肿瘤的保护性T细胞介导的免疫（8，9）。这些细胞现在被用于引发和扩增对人类癌症特异性的T细胞（参考文献10）。10 - 12;也可参见Yu和Restifo，本透视系列，参考文献13）。应答性T细胞包括辅助细胞，特别是Th1 CD4+细胞，其产生IFN-γ;和杀伤细胞，特别是CD8+细胞溶解性T淋巴细胞（CTL），其胞吐富含穿孔素和颗粒酶的颗粒。新的信息表明，DC控制其他类型的淋巴细胞（B、NK和NKT细胞）的反应，并引发T细胞记忆，这是疫苗接种的关键目标。表1疫苗生物学中的挑战需要改进对抗原呈递的控制开发利用DC进行疫苗接种的能力似乎在面对感染因子时特别紧迫，如HIV-1，在安全性方面提出了不寻常的要求;随着疫苗生物学家转向确定的抗原，复制不良的载体和DNA，微生物减毒的历史悠久的方法现在被搁置一边。这些疫苗虽然引入了外源微生物产物，但往往产生较弱的免疫力，尤其是T细胞介导的免疫力。因此，需要更多地强调潜在的免疫过程，特别是DC的强佐剂作用。有趣的是，正如我们在下面讨论的，即使是经典的微生物减毒疫苗方法，成功地用于天花和麻疹，也可能在不知不觉中利用了DC的佐剂作用。
The challenges to vaccine biology are dramatized by the current situation with an AIDS vaccine (see Letvin, this Perspective series, ref. 1). For years, data have been available on the HIV-1 genome and its proteins, as well as numerous antigens recognized by the immune system. Still, this information has not been readily translated into candidate vaccines that induce the broad and long-lasting T cell–mediated immunity thought to be necessary to protect people from acquiring AIDS (2–5). Vaccines are also lacking for many other serious infections in which T cell–mediated immunity should be protective. These include pathogens whose genomic sequences and antigenic proteins are well characterized: tuberculosis, malaria, and the herpes simplex, papilloma, Epstein-Barr, and hepatitis C viruses. In essence, the identification of foreign antigens is necessary but not sufficient for producing vaccines that are effective in the T cell sphere. Better vaccine delivery and vaccine adjuvants, or enhancers of immunity, are required (6, 7). We propose that dendritic cell (DC) physiology should be considered and exploited in meeting each of the challenges in vaccine biology that lie ahead (see Table Table1).1). DCs act as nature’s adjuvants for regulating antigen-specific immunity. As antigen-presenting cells, DCs capture antigens, process them into peptides, and present them on products of the MHC to T cells. DCs are both efficient and specialized in antigen presentation, and they control the magnitude, quality, and memory of the ensuing immune response. DCs have been used successfully as cellular adjuvants in mice to elicit protective T cell–mediated immunity against pathogens and tumors (8, 9). These cells are now being used to prime and expand T cells specific for human cancers (refs. 10–12; see also Yu and Restifo, this Perspective series, ref. 13). The responding T cells include helper cells, especially Th1 CD4+ cells, which produce IFN-γ; and killer cells, especially CD8+ cytolytic T lymphocytes (CTLs), which exocytose granules rich in perforin and granzyme. New information indicates that DCs control responses by other classes of lymphocytes (B, NK, and NKT cells) and elicit T cell memory, a critical goal of vaccination. Table 1 Challenges in vaccine biology requiring improved control of antigen presentation Developing the capacity to harness DCs for vaccination seems particularly urgent in confronting infectious agents that, like HIV-1, pose unusual demands with respect to safety; the time-honored approach of microbial attenuation is now being set aside as vaccine biologists turn to defined antigens, poorly replicating vectors, and DNA. Although these vaccines introduce foreign microbial products, they often generate weak immunity, especially T cell–mediated immunity. Consequently, greater emphasis on underlying immunologic processes is needed, notably the strong adjuvant roles of DCs. Interestingly, as we discuss below, even the classical vaccine approach of microbial attenuation, used successfully for smallpox and measles, may have unknowingly exploited the adjuvant roles of DCs.