Ebensen Thomas, Schulze Kai, Riese Peggy, Morr Michael, Guzmán Carlos A
Department of Vaccinology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany.
Clin Vaccine Immunol. 2007 Aug;14(8):952-8. doi: 10.1128/CVI.00119-07. Epub 2007 Jun 13.
The development of mucosal adjuvants is still a critical need in vaccinology. In the present work, we show that bis(3',5')-cyclic dimeric GMP (cdiGMP), a second messenger that modulates cell surface properties of several microorganisms, exerts potent activity as a mucosal adjuvant. BALB/c mice were immunized intranasally with the model antigen beta-galactosidase (beta-Gal) coadministered with cdiGMP. Animals receiving cdiGMP as an adjuvant showed significantly higher anti-beta-Gal immunoglobulin G (IgG) titers in sera than controls (i.e., 512-fold [P < 0.05]). Coadministration of cdiGMP also stimulated efficient beta-Gal-specific secretory IgA production in the lung (P < 0.016) and vagina (P < 0.036). Cellular immune responses were observed in response to both the beta-Gal protein and a peptide encompassing its major histocompatibility complex class I-restricted epitope. The IgG1-to-IgG2a ratio of anti-beta-Gal antibodies and the observed profiles of secreted cytokines suggest that a dominant Th1 response pattern is promoted by mucosal coadministration of cdiGMP. Finally, the use of cdiGMP as a mucosal adjuvant also led to the stimulation of in vivo cytotoxic T-lymphocyte responses in C57BL/6 mice intranasally immunized with ovalbumin and cdiGMP (up to 30% of specific lysis). The results obtained indicate that cdiGMP is a promising tool for the development of mucosal vaccines.
黏膜佐剂的研发仍然是疫苗学中的一项迫切需求。在本研究中，我们发现双（3'，5'）-环二聚鸟苷酸（cdiGMP）作为一种调节多种微生物细胞表面特性的第二信使，具有作为黏膜佐剂的强大活性。将模型抗原β-半乳糖苷酶（β-Gal）与cdiGMP共同经鼻内免疫BALB/c小鼠。接受cdiGMP作为佐剂的动物血清中抗β-Gal免疫球蛋白G（IgG）滴度显著高于对照组（即高512倍[P<0.05]）。cdiGMP的共同给药还刺激了肺（P<0.016）和阴道（P<0.036）中高效的β-Gal特异性分泌型IgA产生。观察到针对β-Gal蛋白及其包含主要组织相容性复合体I类限制性表位的肽的细胞免疫反应。抗β-Gal抗体的IgG1与IgG2a比值以及观察到的分泌细胞因子谱表明，黏膜共同给药cdiGMP促进了主要的Th1反应模式。最后，将cdiGMP用作黏膜佐剂还导致在用卵清蛋白和cdiGMP经鼻内免疫的C57BL/6小鼠中刺激了体内细胞毒性T淋巴细胞反应（特异性裂解高达30%）。获得的结果表明，cdiGMP是开发黏膜疫苗的一种有前景的工具。
