Ushio H, Tsuji R F, Szczepanik M, Kawamoto K, Matsuda H, Askenase P W
Department of Veterinary Surgery, University of Osaka Prefecture College of Agriculture, Japan.
J Immunol. 1998 Mar 1;160(5):2080-8.
Cutaneous painting with reactive haptens induces contact sensitivity (CS) responses that are in vivo examples of T cell immunity. In contrast, high dose i.v. administration of the hapten can induce tolerance. We investigated the effect of IL-12 on reversal of this tolerance and attempted to determine in vitro the mechanism of this reversing effect by measuring proliferation and IFN-gamma production by CS effector T cells stimulated with hapten-conjugated APC, and we also measured CS ear swelling in vivo. The in vitro responses of T cells to hapten-APC became absent in tolerized mice, paralleling impaired in vivo CS responses. Addition of IL-12 to cultures manifesting this fully established in vitro tolerance completely restored impaired responses of tolerized T cells. The reversing effects of IL-12 were not blocked by anti-IFN-gamma mAb, but were blocked by mAbs against B7-1, more strongly by anti-B7-2, and by both Abs together. Additional in vivo ear-swelling response experiments confirmed the reversing effects of IL-12 on established tolerance. To examine whether the IL-12 effect depended on stimulation of IFN-gamma, we directly injected IFN-gamma into tolerized mice. This partially mimicked but did not fully reconstitute the effects of IL-12. In summary, IL-12 abrogation of established tolerance of CS may have been partially due to endogenous production of IFN-gamma, but appeared mainly due to direct activation of the tolerized T cells by affecting signaling through costimulatory molecules B7-1 and B7-2.
用反应性半抗原进行皮肤涂抹可诱导接触敏感性（CS）反应，这是T细胞免疫的体内实例。相比之下，高剂量静脉注射半抗原可诱导耐受。我们研究了IL-12对这种耐受逆转的影响，并试图通过测量经半抗原偶联的抗原呈递细胞（APC）刺激的CS效应T细胞的增殖和IFN-γ产生，在体外确定这种逆转作用的机制，我们还在体内测量了CS耳部肿胀。在耐受小鼠中，T细胞对半抗原-APC的体外反应消失，这与体内CS反应受损情况相似。向表现出这种完全建立的体外耐受的培养物中添加IL-12，可完全恢复耐受T细胞受损的反应。IL-12的逆转作用未被抗IFN-γ单克隆抗体阻断，但被抗B7-1单克隆抗体阻断，被抗B7-2单克隆抗体更强烈地阻断，且被两种抗体共同阻断。额外的体内耳部肿胀反应实验证实了IL-12对已建立的耐受的逆转作用。为了检查IL-12的作用是否依赖于IFN-γ的刺激，我们将IFN-γ直接注射到耐受小鼠体内。这部分模拟了但并未完全重建IL-12的作用。总之，IL-12消除已建立的CS耐受可能部分归因于内源性IFN-γ的产生，但主要似乎是由于通过共刺激分子B7-1和B7-2影响信号传导直接激活了耐受的T细胞。
