Characterization of Novel Mucosal Modulator for IgA

这项由日本文部科学省支持的国际合作研究项目的一个主要目标是开发新一代疫苗，即下个世纪预防传染病的“粘膜疫苗”。为了实现这一目标，我们的工作重点是开发和表征新的粘膜佐剂，因为已经证明口服和/或鼻免疫蛋白疫苗抗原需要共同施用粘膜增强分子以诱导最大的抗原特异性免疫反应。与阿拉巴马大学伯明翰分校免疫生物学疫苗中心（Jerry R. McGhee教授）和东京国立传染病研究所（Yoshifumi Takeda所长）的研究人员一起，我们成功地产生了两种形式的突变霍乱毒素（mCT），称为S61F和E112K，它们不具有毒性，但保持佐剂活性。这两种mct维持了原生或更多CT的能力，以支持Th2型细胞驱动的粘膜IgA和全身IgG反应。当这些mCT与新的肺炎链球菌疫苗候选抗原PspA一起经鼻给药小鼠时，高水平的抗原特异性分泌IgA和血清IgG抗体对体内攻击提供保护性免疫。上述结果提示，S61F和E112K可作为新一代粘膜佐剂，诱导对不同形式感染的保护性免疫。我们目前的努力也旨在阐明mCT粘膜佐剂活性的分子和细胞机制。我们最近的研究结果表明，mCT调节抗原提呈细胞上共刺激分子如B7-1和B7-2的表达，以诱导和调节抗原特异性免疫反应。最后，我们的研究最近扩展到研究细胞因子在粘膜佐剂中的潜在应用。值得注意的是，鼻腔联合给药IL-12支持抗原特异性iga免疫反应。这一发现为IL-12作为粘膜细胞因子在体内诱导和调控疫苗抗原特异性免疫应答提供了新的可能性。这些有趣而重要的发现发表在高质量的国际期刊上（例如，J. Exp. Med., Proc. Natl.）。学会科学。美国。，自然医学，J.免疫。等)。通过这一国际合作项目，我们在两年的资助期内共在这些期刊上发表了44篇论文。少

A major goal of this International Collaboration Research Project supported by the Ministry of Education, Science, Sports and Culture of Japan was to develop new generation vaccine, namely "Mucosal Vaccine" for the prevention of infectious diseases in next century. To accomplish this goal, our efforts was focused on the development and characterization of new mucosal adjubant since it has been shown the oral and/or nasal immunization of protein vaccine antigen required co-administration of mucosal enhancing molecule for the induction of maximum antigen-specific immune response. Together with investigators in Immunobiology Vaccine Center the University of Alabama at Birmingham (Prof. Jerry R. McGhee) and National Institute of Infectious Diseases of Tokyo (Director, Yoshifumi Takeda), we have successfully generated two forms of mutant cholera toxin (mCT) known as S61F and E112K which do not possess toxicity but maintain adjuvant activity. These two mCTs maintained an ability of native fo … More rm of CT for supporting Th2 type cell driven mucosal IgA and systemic IgG responses. When these mCT were given together with new S. pneumoniae vaccine antigen candidate, PspA to mice via nasal route, high levels of antigen-specific secretory IgA and serum IgG antibody provided protective immunity against in vivo challenge. These findings suggested that S61F and E112K can be used as new generation of mucosal adjuvant for the induction of protective immunity against different forms of infection. Our current effort is also aimed to the elucidation of molecular and cellular mechanisms for the mucosal adjuvant activity of mCT. Our recent results suggest that mCT regulate expression of co-stimalatory molecules, such as B7-1 and B7-2 on antigen presenting cells for the induction and regulation of antigen-specific immune response. Finally, our study is recently extended to examine potential application of cytokine for mucosal adjuvant. It was interesting to note that nasally co-administered IL-12 supported antigen-specific-IgA immune responses. This finding provide new possibility that IL-12 can be used as mucosal cytokine for the induction and regulation of vaccine antigen-specific immune response in vivo. These interesting and important findings wore published in high quality international journals (e. g., J. Exp. Med., Proc. Natl. Acad. Sci. USA., Nature Med., J. Immunol. and etc). Through this international collaboration project, a total of 44pepars was published in these journals by our efforts provided in this two years grant funded period. Less