Kato H, Fujihashi K, Kato R, Yuki Y, McGhee J R
Department of Microbiology, Immunobiology Vaccine Center, University of Alabama, Birmingham, AL 35294, USA.
J Immunol. 2001 Mar 1;166(5):3114-21. doi: 10.4049/jimmunol.166.5.3114.
Oral delivery of a large dose or prolonged feeding of protein Ags induce systemic unresponsiveness most often characterized as reduced IgG and IgE Ab- and Ag-specific CD4(+) T cell responses. It remains controversial whether oral tolerance extends to diminished mucosal IgA responses in the gastrointestinal tract. To address this issue, mice were given a high oral dose of OVA or PBS and then orally immunized with OVA and cholera toxin as mucosal adjuvant, and both systemic and mucosal immune responses were assessed. OVA-specific serum IgG and IgA and mucosal IgA Ab levels were markedly reduced in mice given OVA orally compared with mice fed PBS. Furthermore, when OVA-specific Ab-forming cells (AFCs) in both systemic and mucosa-associated tissues were examined, IgG AFCs in the spleen and IgA AFCs in the gastrointestinal tract lamina propria of mice given OVA orally were dramatically decreased. Furthermore, marked reductions in OVA-specific CD4(+) T cell proliferative and cytokine responses in spleen and Peyer's patches were seen in mice given oral OVA but were unaffected in PBS-fed mice. We conclude that high oral doses of protein induce both mucosal and systemic unresponsiveness and that use of mucosal adjuvants that induce both parenteral and mucosal immunity may be a better way to assess oral tolerance.
口服大剂量蛋白质抗原或长期喂食蛋白质抗原通常会诱导全身无反应性，其最常见的特征是IgG和IgE抗体及抗原特异性CD4(+) T细胞反应降低。口服耐受是否会导致胃肠道黏膜IgA反应减弱仍存在争议。为了解决这个问题，给小鼠口服高剂量的卵清蛋白（OVA）或磷酸盐缓冲盐水（PBS），然后用OVA和霍乱毒素作为黏膜佐剂进行口服免疫，并评估全身和黏膜免疫反应。与喂食PBS的小鼠相比，口服OVA的小鼠中OVA特异性血清IgG和IgA以及黏膜IgA抗体水平明显降低。此外，当检测全身和黏膜相关组织中的OVA特异性抗体形成细胞（AFC）时，口服OVA的小鼠脾脏中的IgG AFC和胃肠道固有层中的IgA AFC显著减少。此外，口服OVA的小鼠脾脏和派尔集合淋巴结中OVA特异性CD4(+) T细胞增殖和细胞因子反应明显降低，但喂食PBS的小鼠则不受影响。我们得出结论，口服高剂量蛋白质会诱导黏膜和全身无反应性，使用既能诱导肠道外免疫又能诱导黏膜免疫的黏膜佐剂可能是评估口服耐受的更好方法。
