Pascual D W, Hone D M, Hall S, van Ginkel F W, Yamamoto M, Walters N, Fujihashi K, Powell R J, Wu S, Vancott J L, Kiyono H, McGhee J R
Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717-3610, USA.
Infect Immun. 1999 Dec;67(12):6249-56. doi: 10.1128/IAI.67.12.6249-6256.1999.
Protective immunity to enterotoxigenic Escherichia coli (ETEC) is antibody (Ab) dependent; however, oral immunization with purified ETEC fimbriae fails to elicit protective immunity as a consequence of antigenic alteration by the gastrointestinal (GI) tract. Unless unaltered ETEC fimbriae can reach the inductive lymphoid tissues of the GI tract, immunity to ETEC cannot be induced. To produce immunity, live vectors, such as Salmonella typhimurium, can effectively target passenger antigens to the inductive lymphoid tissues of the GI tract. By convention, oral immunizations with Salmonella vectors induce CD4(+) T helper (Th) cell responses by gamma interferon (IFN-gamma)-dominated pathways both to the vector and passenger antigen, resulting in serum immunoglobulin G2a (IgG2a) and modest mucosal IgA Ab responses. In the present study, mice orally immunized with a Salmonella vector engineered to stably express ETEC colonization factor antigen I (CFA/I) showed initially elevated serum IgG1 and mucosal IgA anti-CFA/I Ab responses. As expected, mice orally immunized with an E. coli-CFA/I construct elicited poor anti-CFA/I Ab responses. In fact, the addition of cholera toxin during oral E. coli-CFA/I immunization failed to greatly enhance mucosal IgA Ab responses. Seven days after immunization with the Salmonella-CFA/I construct, cytokine-specific ELISPOT showed induction of predominant Th2-type responses in both mucosal and systemic immune compartments supporting the early IgG1 and IgA anti-CFA/I Abs. By 4 weeks, the Th cell response became Th1 cell dominant from the earlier Th2-type responses, as evidenced by increased mucosal and systemic IFN-gamma-producing T cells and a concomitant elevation of serum IgG2a Ab responses. This biphasic response offers an alternative strategy for directing Salmonella vector-induced host immunity along a Th2 cell-dependent pathway, allowing for early promotion of mucosal and systemic Abs.
对产肠毒素大肠杆菌（ETEC）的保护性免疫是抗体（Ab）依赖性的；然而，由于胃肠道（GI）对抗原的改变，用纯化的ETEC菌毛进行口服免疫无法引发保护性免疫。除非未改变的ETEC菌毛能够到达胃肠道的诱导性淋巴组织，否则无法诱导对ETEC的免疫。为了产生免疫，活载体，如鼠伤寒沙门氏菌，可以有效地将乘客抗原靶向胃肠道的诱导性淋巴组织。按照惯例，用沙门氏菌载体进行口服免疫会通过以γ干扰素（IFN-γ）为主导的途径诱导针对载体和乘客抗原的CD4(+)辅助性T（Th）细胞反应，从而产生血清免疫球蛋白G2a（IgG2a）和适度的黏膜IgA抗体反应。在本研究中，用经工程改造稳定表达ETEC定植因子抗原I（CFA/I）的沙门氏菌载体口服免疫的小鼠，最初血清IgG1和黏膜IgA抗CFA/I抗体反应升高。正如预期的那样，用大肠杆菌-CFA/I构建体口服免疫的小鼠引发的抗CFA/I抗体反应较差。事实上，在口服大肠杆菌-CFA/I免疫期间添加霍乱毒素并不能显著增强黏膜IgA抗体反应。用沙门氏菌-CFA/I构建体免疫7天后，细胞因子特异性ELISPOT显示在黏膜和全身免疫区室中均诱导了主要的Th2型反应，这支持了早期的IgG1和IgA抗CFA/I抗体。到4周时，Th细胞反应从早期的Th2型反应转变为Th1细胞主导，表现为黏膜和全身产生IFN-γ的T细胞增加以及血清IgG2a抗体反应随之升高。这种双相反应为沿着Th2细胞依赖性途径引导沙门氏菌载体诱导的宿主免疫提供了一种替代策略，从而能够早期促进黏膜和全身抗体的产生。
