Kweon M-N, Takahashi I, Yamamoto M, Jang M H, Suenobu N, Kiyono H
Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565, Japan.
Gut. 2002 Mar;50(3):299-306. doi: 10.1136/gut.50.3.299.
Enteric bacterial and/or food antigens may be crucial in the development of colitis but little is known of the exact mechanism of antigen specific reactions in this condition. The aim of this study was to determine whether systemically primed antigen specific CD4(+) T cells containing both CD45RB(high) and CD45RB(low) populations participate as a pathogenic subset that in turn leads to inflammatory reactions selectively in the large intestine.
SCID mice were reconstituted with splenic CD4(+) CD45RB(+) T cells or CD4(+) CD45RB(low) T cells isolated from donor mice systemically primed with ovalbumin (OVA) plus CFA. The reconstituted mice were then fed OVA for several weeks.
Reconstitution of SCID mice with OVA primed splenic CD4(+) T cells, containing populations of CD45RB(high) and CD45RB(low), resulted in the development of colitis by 4-5 weeks following repeated administration of oral OVA. Histopathological study revealed thickened wall, inflammatory cell infiltration, crypt elongation, and loss of goblet cells in the large intestine. The CD4(+) CD45RB(low) population of cells extracted from the affected large intestine secreted high levels of interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) at the protein and mRNA levels. Administration of neutralising antibodies to TNF-alpha, but not to IFN-gamma, prevented the development of colitis. Furthermore, adoptive transfer with OVA primed splenic CD4(+) CD45RB(low) T cells evoked severe colitis.
These results demonstrate that systemically primed activated/memory CD4(+) CD45RB(low) T cells can mediate the development of specific antigen induced colitis in SCID mice, and also that TNF-alpha is critical in the induction of this type of colitis. Our results contrast with those from studies in some colitis models in which CD45RB(low) T cells appeared to prevent colitis through secretion of immunosuppressive cytokines.
肠道细菌和/或食物抗原可能在结肠炎的发生发展中起关键作用，但对于这种情况下抗原特异性反应的确切机制知之甚少。本研究的目的是确定全身致敏的同时含有CD45RB(高)和CD45RB(低)群体的抗原特异性CD4(+) T细胞是否作为致病亚群参与其中，进而导致大肠选择性地发生炎症反应。
用从经卵清蛋白（OVA）加完全弗氏佐剂全身致敏的供体小鼠中分离出的脾CD4(+) CD45RB(+) T细胞或CD4(+) CD45RB(低) T细胞重建重症联合免疫缺陷（SCID）小鼠。然后给重建后的小鼠喂食OVA数周。
用OVA致敏的同时含有CD45RB(高)和CD45RB(低)群体的脾CD4(+) T细胞重建SCID小鼠，在反复口服OVA后4至5周会发生结肠炎。组织病理学研究显示大肠壁增厚、炎性细胞浸润、隐窝延长和杯状细胞丢失。从受影响的大肠中提取的CD4(+) CD45RB(低)细胞群体在蛋白质和mRNA水平上分泌高水平的干扰素γ（IFN-γ）和肿瘤坏死因子α（TNF-α）。给予抗TNF-α中和抗体可预防结肠炎的发生，但给予抗IFN-γ中和抗体则不能。此外，用OVA致敏的脾CD4(+) CD45RB(低) T细胞进行过继转移可诱发严重的结肠炎。
这些结果表明，全身致敏的活化/记忆性CD4(+) CD45RB(低) T细胞可介导SCID小鼠中特异性抗原诱导的结肠炎的发生，并且TNF-α在这种类型结肠炎的诱导中起关键作用。我们的结果与一些结肠炎模型研究的结果形成对比，在那些模型中CD45RB(低) T细胞似乎通过分泌免疫抑制细胞因子来预防结肠炎。
