Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis.
Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis.
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DOI：
10.1084/jem.189.2.219
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发表时间：
1999-01-18
期刊：
影响因子：
--
通讯作者：
Caspi RR
中科院分区：
文献类型：
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作者：
Tarrant TK;Silver PB;Wahlsten JL;Rizzo LV;Chan CC;Wiggert B;Caspi RR
实验性自身免疫性葡萄膜炎（EAU）中的致病性效应T细胞是1型T辅助细胞样细胞，其产生和功能需要白细胞介素（IL）-12。因此，我们预期IL-12给药将具有疾病增强作用。用视网膜抗原感光细胞间类维生素A结合蛋白的致葡萄膜方案免疫小鼠，用IL-12（100 ng/d，持续5 d）处理，并通过组织病理学评估EAU。出乎意料的是，IL-12治疗未能增强耐药菌株中的EAU和下调易感菌株中的疾病。只有在免疫后第一周内进行治疗，而不是在第二周内进行治疗，才具有持续的保护作用。在IL-12治疗期间，血清中存在高水平的干扰素γ（IFN-γ），但随后受保护小鼠中抗原特异性IFN-γ的产生减少，IL-5的产生、淋巴结细胞增殖和血清抗体水平也减少。经治疗的小鼠在引流淋巴结中具有更少的细胞和增强的细胞凋亡的证据。与野生型小鼠不同，IFN-γ缺陷型、诱导型一氧化氮合酶（iNOS）缺陷型和Bcl-2lck转基因小鼠受IL-12保护较差，而IL-10缺陷型小鼠受保护。我们的结论是，IL-12的管理中止疾病的发展，减少葡萄膜效应T细胞。这些数据与以下解释一致：IL-12诱导IFN-γ的全身性过度诱导，引起iNOS的活化和NO的产生，其至少部分地通过在抗原特异性T细胞被致敏时触发Bcl-2调节的抗原特异性T细胞的凋亡缺失来介导保护。
Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1–like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon γ (IFN-γ) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-γ production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-γ–deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2lck transgenic mice were poorly protected by IL-12, whereas IL-10–deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-γ, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.