Tarrant T K, Silver P B, Chan C C, Wiggert B, Caspi R R
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20892, USA.
J Immunol. 1998 Jul 1;161(1):122-7.
Experimental autoimmune uveitis (EAU) has been associated with a Th1 response. However, in IFN-gamma-deficient mice, EAU develops in the context of an effector response having Th2-like elements, and administration of IL-12 to mice immunized for EAU induction can be protective. We, therefore, investigated whether endogenous IL-12 is required for development of EAU. IL-12 p40-deficient mice (12KO) were resistant to EAU induced with the uveitogenic retinal Ag interphotoreceptor retinoid binding protein (IRBP). Delayed hypersensitivity to IRBP was marginally reduced, whereas Ag-specific proliferation was enhanced. Primed lymphocytes of wild-type (wt) mice, cultured with IRBP, produced a Th1-like cytokine profile and transferred EAU to syngeneic wt recipients. Interestingly, the same cells were inefficient in transferring EAU to 12KO recipients, unless IL-12 was included in the culture. Primed cells of the 12KO mice produced a Th2-like cytokine profile and failed to transfer EAU. However, when IL-12 was added to the culture, 12KO cells produced large amounts of IFN-gamma and transferred EAU to naive 12KO recipients. We conclude that resistance to EAU of 12KO mice is not due to an inherent inability of these mice to develop ocular disease. Despite an apparent similarity in Ag-specific cytokine responses to IFN-gamma-deficient mice, 12KO mice have inhibited generation of uveitogenic effector cells, a situation that can be reversed even after priming, by adding exogenous IL-12 ex vivo. Lastly, the diminished ability of primed wt lymphocytes to induce EAU in 12KO mice indicates a role for endogenous IL-12 in the efferent phase of disease expression that is distinct from its role during Ag priming.
实验性自身免疫性葡萄膜炎（EAU）与Th1反应相关。然而，在缺乏干扰素-γ的小鼠中，EAU是在具有Th2样成分的效应反应背景下发生的，并且向免疫诱导EAU的小鼠施用白细胞介素-12具有保护作用。因此，我们研究了EAU的发生是否需要内源性白细胞介素-12。白细胞介素-12 p40缺陷小鼠（12KO）对葡萄膜炎性视网膜抗原视网膜色素上皮间视黄醇结合蛋白（IRBP）诱导的EAU具有抗性。对IRBP的迟发型超敏反应略有降低，而抗原特异性增殖增强。用IRBP培养的野生型（wt）小鼠的致敏淋巴细胞产生Th1样细胞因子谱，并将EAU转移至同基因wt受体。有趣的是，除非培养物中包含白细胞介素-12，否则相同的细胞向12KO受体转移EAU的效率较低。12KO小鼠的致敏细胞产生Th2样细胞因子谱，未能转移EAU。然而，当向培养物中添加白细胞介素-12时，12KO细胞产生大量干扰素-γ，并将EAU转移至未致敏的12KO受体。我们得出结论，12KO小鼠对EAU的抗性并非由于这些小鼠本身无法发生眼部疾病。尽管在对抗原特异性细胞因子的反应上与缺乏干扰素-γ的小鼠有明显相似之处，但12KO小鼠的葡萄膜炎性效应细胞生成受到抑制，这种情况即使在致敏后也可通过体外添加外源性白细胞介素-12来逆转。最后，致敏的wt淋巴细胞在12KO小鼠中诱导EAU的能力降低，表明内源性白细胞介素-12在疾病表达的传出阶段发挥作用，这与其在抗原致敏期间的作用不同。
