Lúdvíksson B R, Strober W, Nishikomori R, Hasan S K, Ehrhardt R O
Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
J Immunol. 1999 Apr 15;162(8):4975-82.
We previously demonstrated that 2,4,6-trinitrophenol (TNP)-OVA immunization leads to a transmural colitis in the IL-2-/- mouse that is caused by IL-12-driven CD4+ Th1 T cells and resembles human Crohn's disease. The integrin alpha E beta 7 is highly expressed on colonic intraepithelial lymphocytes and has been suggested to function as a homing or retention molecule for intraepithelial lymphocytes. To evaluate the role of alpha E beta 7 in colitis, we administered a mAb against alpha E beta 7 to IL-2-/- mice that were immunized at the same time with TNP-OVA in CFA. To our surprise, this treatment resulted in a significantly reduced colitis severity score, 0-2 vs 3-4, that was associated with a significant reduction in CD4+ lamina propria lymphocyte subpopulation (p < 0.01). In contrast, the total number of splenic CD4+ T cells of treated animals was significantly elevated compared with that of untreated animals (3.2 +/- 0.6 x 107 vs 1.2 +/- 0.2 x 107; p < 0.05). Similarly, functional studies revealed that IFN-gamma production by lamina propria lymphocytes isolated from IL-2-/- TNP-OVA-immunized mice treated with anti-alpha E beta 7 was significantly lower than in untreated IL-2-/- TNP-OVA-immunized mice. In contrast, IFN-gamma production by splenic cells isolated from treated IL-2-/- TNP-OVA-immunized mice was significantly higher than in untreated mice. Finally, TNP-OVA-immunized IL-2-/- mice that were treated after the colitis had been established also showed a significant decrease in mucosal inflammation after alpha E beta 7 mAb administration. Thus, the above findings demonstrate that the onset and maintenance of inflammatory bowel disease depends on the colonic localization of lamina propria CD4+ lymphocytes expressing alpha E beta 7.
我们之前证明，2,4,6-三硝基苯酚（TNP）-卵清蛋白（OVA）免疫可导致IL-2基因敲除小鼠发生透壁性结肠炎，该结肠炎由IL-12驱动的CD4⁺ Th1 T细胞引起，类似于人类克罗恩病。整合素αEβ7在结肠上皮内淋巴细胞上高度表达，有人认为它作为上皮内淋巴细胞的归巢或滞留分子发挥作用。为了评估αEβ7在结肠炎中的作用，我们给IL-2基因敲除小鼠注射了抗αEβ7单克隆抗体，这些小鼠同时在完全弗氏佐剂（CFA）中用TNP-OVA进行免疫。令我们惊讶的是，这种治疗使结肠炎严重程度评分显著降低，从3 - 4分降至0 - 2分，这与固有层CD4⁺淋巴细胞亚群显著减少相关（p < 0.01）。相反，与未治疗动物相比，治疗动物脾脏CD4⁺ T细胞总数显著升高（3.2 ± 0.6×10⁷ 对1.2 ± 0.2×10⁷；p < 0.05）。同样，功能研究表明，从用抗αEβ7治疗的IL-2基因敲除TNP-OVA免疫小鼠分离的固有层淋巴细胞产生的γ干扰素显著低于未治疗的IL-2基因敲除TNP-OVA免疫小鼠。相反，从用抗αEβ7治疗的IL-2基因敲除TNP-OVA免疫小鼠分离的脾细胞产生的γ干扰素显著高于未治疗小鼠。最后，在结肠炎已形成后接受治疗的TNP-OVA免疫IL-2基因敲除小鼠在给予αEβ7单克隆抗体后也显示黏膜炎症显著减轻。因此，上述发现表明炎症性肠病的发生和维持取决于表达αEβ7的固有层CD4⁺淋巴细胞在结肠的定位。
