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，即用于下个世纪预防传染病的“粘膜疫苗”。为了实现这一目标，我们的努力集中在新的黏膜佐剂的开发和表征上，因为已经表明，蛋白质疫苗抗原的口服和/或鼻腔免疫需要黏膜增强分子的共同作用，以诱导最大的抗原特异性免疫反应。我们与伯明翰阿拉巴马大学免疫生物学疫苗中心的研究人员(曾傑瑞·R·麦基教授)和东京国立传染病研究所的研究员(武田洋文教授)一起，成功培育出了两种被称为S61F和E112K的霍乱毒素突变株，它们无毒性，但仍保持佐剂活性。这两个MCT保持了原生fo…的能力更多的CT支持Th2型细胞驱动的粘膜免疫球蛋白A和系统免疫球蛋白G反应。当这些MCT与新的肺炎链球菌疫苗候选抗原PSPA经鼻腔给药时，高水平的抗原特异性分泌型IgA和血清抗体对体内攻击具有保护性免疫作用。这些结果表明，S61F和E112K可作为新一代粘膜佐剂用于诱导对不同形式感染的保护性免疫。我们目前的工作也旨在阐明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可以调节抗原提呈细胞表面共刺激分子B7-1和B7-2的表达，从而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检测细胞因子作为粘膜佐剂的潜在应用。有趣的是，鼻腔联合注射IL-12可支持抗原特异性IgA免疫反应。这一发现为IL-12作为黏膜细胞因子在体内诱导和调节疫苗抗原特异性免疫反应提供了新的可能性。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。医学部，过程娜塔莉。阿卡德。SCI。美国，自然医学，J.免疫。等等)。通过这一国际合作项目，在这两年的资助期内，通过我们的努力，在这些期刊上总共发表了44篇PEPAR。较少

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