Holmgren J, Czerkinsky C, Lycke N, Svennerholm A M
Department of Medical Microbiology and Immunology, University of Goteborg, Sweden.
Am J Trop Med Hyg. 1994;50(5 Suppl):42-54.
The concept of a common mucosal immune system, through which specific antigen-activated lymphocytes from the gut can disseminate immunity both along the intestinal tract and to various other mucosal and glandular tissues, has generated much current interest in the possibility of developing oral vaccines, not only for enteric infections but also for infections in the respiratory and urogenital tracts. However, to date it has proven difficult in practice to stimulate strong mucosal IgA immune responses by either parenteral or oral-mucosal administration of most antigens, and experience with soluble protein antigens has, on the whole, been disappointing. A notable exception in this regard is cholera toxin (CT) and in humans more than in other species, its nontoxic B subunit pentamer moiety (CTB). Based on this, CTB has become an important component in recently developed oral vaccines against cholera as well as against diarrhea caused by enterotoxigenic Escherichia coli producing CT-like heat-labile enterotoxin(s). Since the strong immunogenicity of CT and CTB can, to a large extent, be explained by their ability to bind to receptors on the intestinal mucosal surface, there has recently been much interest in approaches using CTB as an oral delivery carrier system for other vaccine-relevant antigens, and much progress has been made in preparing immunogenic hybrid proteins by coupling various protein or peptide antigens chemically or genetically to CTB. Indeed, in several systems, oral administration of such hybrid antigens has been found to markedly potentiate both intestinal and extraintestinal IgA immune responses against the CTB-coupled antigens and also to elicit substantial circulating antibody responses. Besides the mucosal immunopotentiating effect of either CT or CTB owing to their similar capacity as oral antigen-delivery vehicles, CT, but in most systems tested not CTB, also has strong adjuvant properties for stimulating mucosal IgA immune responses to admixed (not coupled) unrelated antigens after oral immunization. This adjuvant activity appears to be closely linked to the ADP-ribosylating action of CT (and specifically of its A subunit) leading to enhanced cyclic AMP formation in the affected cell, and efforts to eliminate the enterotoxic activity without losing adjuvanticity have so far not met with success.
共同黏膜免疫系统的概念认为，来自肠道的特定抗原激活淋巴细胞可沿肠道以及向其他各种黏膜和腺组织传播免疫，这引发了当前人们对开发口服疫苗可能性的极大兴趣，不仅用于肠道感染，还用于呼吸道和泌尿生殖道感染。然而，迄今为止，事实证明，通过肠胃外或口服黏膜方式给予大多数抗原，在实践中难以刺激强烈的黏膜IgA免疫反应，总体而言，可溶性蛋白质抗原的经验令人失望。在这方面一个显著的例外是霍乱毒素（CT），在人类中比在其他物种中更是如此，其无毒B亚基五聚体部分（CTB）。基于此，CTB已成为最近开发的抗霍乱以及抗由产生CT样热不稳定肠毒素的产肠毒素大肠杆菌引起的腹泻的口服疫苗的重要成分。由于CT和CTB的强免疫原性在很大程度上可由它们与肠道黏膜表面受体的结合能力来解释，最近人们对将CTB用作其他疫苗相关抗原的口服递送载体系统的方法产生了浓厚兴趣，并且在通过化学或基因方式将各种蛋白质或肽抗原与CTB偶联来制备免疫原性杂合蛋白方面取得了很大进展。事实上，在几个系统中，已发现口服给予此类杂合抗原可显著增强针对CTB偶联抗原的肠道和肠道外IgA免疫反应，还可引发大量循环抗体反应。除了CT或CTB因其作为口服抗原递送载体的相似能力而具有的黏膜免疫增强作用外，CT（但在大多数测试系统中不是CTB）在口服免疫后对刺激针对混合（未偶联）无关抗原的黏膜IgA免疫反应也具有很强佐剂特性。这种佐剂活性似乎与CT（特别是其A亚基）的ADP核糖基化作用密切相关，导致受影响细胞中环状AMP形成增加，并且迄今为止，在不丧失佐剂活性的情况下消除肠毒素活性的努力尚未成功。
