Suzuki Hideaki, Sekine Shinichi, Kataoka Kosuke, Pascual David W, Maddaloni Massimo, Kobayashi Ryoki, Fujihashi Keiko, Kozono Haruo, McGhee Jerry R, Fujihashi Kohtaro
Department of Pediatric Dentistry, The Immunobiology Vaccine Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
Gastroenterology. 2008 Sep;135(3):917-25. doi: 10.1053/j.gastro.2008.05.037. Epub 2008 May 15.
BACKGROUND & AIMS: The follicle-associated epithelium (FAE) plays key roles in antigen uptake and subsequent induction of mucosal immunity. In this study, we examined whether M-cell targeting using a protein antigen (Ag) delivery system would induce oral tolerance instead of enhancement of Ag-specific mucosal antibody (Ab) responses.
Mice were fed different doses of a recombinant protein sigma 1 of reovirus genetically conjugated to ovalbumin (OVA-psigma1), psigma1 only, or phosphate-buffered saline (PBS) before oral challenge with OVA plus cholera toxin as mucosal adjuvant. OVA-specific Ab and CD4-positive (CD4(+)) T-cell responses were determined.
A low dose of OVA-psigma1 reduced anti-OVA Ab and CD4(+) T-cell responses in both mucosal and systemic lymphoid tissues. OVA/MHC I-A(d) tetramer staining showed that the numbers of OVA-specific CD4(+) T cells were significantly reduced in lamina propria of mice fed OVA-psigma1 than those fed psigma1 only or PBS only. In fact, Foxp3 expressing CD25(+) CD4(+) T cells were markedly increased in this tissue. Nonetheless, CD25(+) CD4(+) T cells from the spleen, mesenteric lymph nodes, and Peyer's patches of orally tolerized mice showed increased transforming growth factor beta1 (TGF-beta1) and interleukin-10 (IL-10) production compared with nontolerized mice.
These results show that an FAE M-cell targeting protein Ag delivery system facilitates oral tolerance induction because of a reduction in Ag-specific CD4(+) T cells and increased levels of TGF-beta1 and IL-10 producing, CD25(+) CD4(+) regulatory T cells in both systemic and mucosal lymphoid tissues.
滤泡相关上皮（FAE）在抗原摄取及随后的黏膜免疫诱导中起关键作用。在本研究中，我们检测了使用蛋白质抗原（Ag）递送系统靶向M细胞是否会诱导口服耐受而非增强Ag特异性黏膜抗体（Ab）反应。
在用OVA加霍乱毒素作为黏膜佐剂进行口服攻击前，给小鼠喂食不同剂量的与卵清蛋白（OVA）基因偶联的呼肠孤病毒重组蛋白sigma 1（OVA-psigma1）、仅psigma1或磷酸盐缓冲盐水（PBS）。测定OVA特异性Ab和CD4阳性（CD4(+)）T细胞反应。
低剂量的OVA-psigma1降低了黏膜和全身淋巴组织中的抗OVA Ab及CD4(+) T细胞反应。OVA/MHC I-A(d)四聚体染色显示，喂食OVA-psigma1的小鼠固有层中OVA特异性CD4(+) T细胞数量显著少于仅喂食psigma1或仅喂食PBS的小鼠。事实上，该组织中表达Foxp3的CD25(+) CD4(+) T细胞明显增加。尽管如此，与未耐受小鼠相比，口服耐受小鼠脾脏、肠系膜淋巴结和派尔集合淋巴结中的CD25(+) CD4(+) T细胞产生的转化生长因子β1（TGF-β1）和白细胞介素10（IL-10）增加。
这些结果表明，由于全身和黏膜淋巴组织中Ag特异性CD4(+) T细胞减少以及产生TGF-β1和IL-10的CD25(+) CD4(+)调节性T细胞水平增加，FAE M细胞靶向蛋白质Ag递送系统促进了口服耐受的诱导。
