Induction and prevention of colonic inflammation in IL-2-deficient mice.
Induction and prevention of colonic inflammation in IL-2-deficient mice.
复制标题
IL-2 缺陷小鼠结肠炎症的诱导和预防。
作者：
Rolf O. Ehrhardt;B. Ludviksson;B. Gray;M. Neurath;Warren Strober
缺乏IL-2基因的小鼠（IL-2 -/-小鼠）在无菌条件下维持时没有明显的疾病，但在常规环境中发展结肠炎和自身免疫。本研究表明，通过免疫CFA中的Ag，可以在IL-2 -/-小鼠中再现性地诱导结肠炎，但在IL-2 +/+小鼠中却不能；从而对结肠炎的免疫发病机制进行了系统的研究。我们发现，TNP-KLH或TNP-OVA在诱导结肠炎方面具有最显著的作用，虽然TNP-KLH免疫导致IL-2 -/-和IL-2 +/+小鼠结肠中早期出现活化T细胞，但只有IL-2 -/-小鼠的固有层细胞产生大量的inf - γ。此外，浸润性结肠CD4+(69%)和CD8+ (6%) T细胞分泌大量ifn - γ；然而，只有CD4+ T细胞的消耗才能导致炎症的消除。在进一步的分析中，我们发现高ifn - γ的产生是由IL-12驱动的，因为IL-2 -/-小鼠的结肠组织中存在异二聚体IL-12，而IL-2 +/+小鼠的结肠组织中不存在异二聚体IL-12，抗IL-12与TNP-KLH共同给药可以完全预防结肠炎并显着降低ifn - γ的产生。最后，我们证明了IL-2 -/-小鼠在tnf - klh攻击后诱导Th2反应的能力不足，并且这种免疫也导致IL-2 -/-小鼠的其他器官出现自身免疫样现象。这些发现表明，在缺乏IL-2的情况下，Ag主要诱导Th1细胞过度表达异二聚体IL-12。
Gene-targeted mice deficient for IL-2 (IL-2 -/- mice) are free of apparent disease when maintained under germfree conditions but develop colitis and autoimmunity in a conventional environment. Here we show that colitis can be reproducibly induced in IL-2 -/- mice, but not in IL-2 +/+ mice, by i.p. immunization with Ag in CFA; thus enabling the systematic study of the immunopathogenesis of the colitis. We found that TNP-KLH or TNP-OVA had the most significant effect in inducing colitis, and while TNP-KLH immunization leads to the early appearance of activated T cells in the colons of both IL-2 -/- and IL-2 +/+ mice, only lamina propria cells of IL-2 -/- mice produced high amounts of INF-gamma. Moreover, both infiltrating colon CD4+ (69%) and CD8+ (6%) T cells secrete large amounts of IFN-gamma; however, only the depletion of CD4+ T cells leads to abrogation of the inflammation. In further analysis, we showed that the high IFN-gamma production is IL-12 driven, since colonic tissues of IL-2 -/- mice but not IL-2 +/+ mice show the presence of heterodimeric IL-12 and co-administration of anti-IL-12 with TNP-KLH completely prevented colitis and significantly reduced IFN-gamma production. Finally, we demonstrate that IL-2 -/- mice are deficient in their ability to induce Th2 responses after TNP-KLH challenge and that such immunization also leads to autoimmune-like phenomena in other organs of IL-2 -/- mice. These findings suggest that in the absence of IL-2 systemic administration of Ag induces primarily Th1 cells driven by overexpression of heterodimeric IL-12.