De Magistris Maria Teresa
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita', Viale Regina Elena 299, 00161 Rome, Italy.
Vaccine. 2006 Apr 12;24 Suppl 2:S2-60-1. doi: 10.1016/j.vaccine.2005.01.123.
Cholera toxin (CT) and CT-related molecules have been known since a long time to act as powerful mucosal adjuvants. We have studied the stimulatory effects of CT on human dendritic cells and its inhibitory activity on T lymphocytes. We have also identified a third bacterial enterotoxin, Zonula occludens toxin (Zot) that acts as an effective mucosal adjuvant. Zonula occludens toxin is produced by Vibrio cholerae and has the property to increase intestinal mucosa permeability by reversibly affecting the structure of tight junctions. We found that recombinant ZOT induces long lasting and protective immunity to intranasally delivered antigens and is effective also through other mucosal routes. Furthermore, ZOT is highly efficacious when compared to the mucosal adjuvant LT (Escherichia coli heat-labile enterotoxin) but has a much lower immunogenicity. By using an octapeptide representing the putative binding site of Zot and of its endogenous analogue Zonulin, we provided evidence that Zot may bind a receptor on the nasal mucosa and may mimic an endogenous regulator of tight junctions to deliver antigens in the submucosa. Finally, we are testing recombinant fragments of ZOT for their mucosal adjuvant activity. In conclusion, Zot and its derivatives are very promising tools for the development of needle-free mucosal vaccines.
霍乱毒素（CT）及相关分子长期以来被认为是强大的黏膜佐剂。我们研究了CT对人树突状细胞的刺激作用及其对T淋巴细胞的抑制活性。我们还鉴定出了第三种细菌肠毒素——小带闭合毒素（Zot），它是一种有效的黏膜佐剂。小带闭合毒素由霍乱弧菌产生，具有通过可逆影响紧密连接结构来增加肠黏膜通透性的特性。我们发现重组ZOT能诱导对经鼻递送抗原的持久保护性免疫，并且通过其他黏膜途径也有效。此外，与黏膜佐剂LT（大肠杆菌不耐热肠毒素）相比，ZOT高效得多，但免疫原性低得多。通过使用代表Zot及其内源性类似物闭合蛋白假定结合位点的八肽，我们证明Zot可能与鼻黏膜上的受体结合，并可能模拟紧密连接的内源性调节因子以在黏膜下层递送抗原。最后，我们正在测试ZOT重组片段的黏膜佐剂活性。总之，Zot及其衍生物是开发无针黏膜疫苗非常有前景的工具。
