Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12.
Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12.
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DOI：
10.1084/jem.181.1.381
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发表时间：
1995-01-01
期刊：
影响因子：
--
通讯作者：
Goldman SJ
中科院分区：
文献类型：
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作者：
Leonard JP;Waldburger KE;Goldman SJ
实验性过敏性脑脊髓炎（EAE）是一种中枢神经系统自身免疫性疾病，可通过从适当免疫小鼠中分离的CD4+ T细胞转移到幼稚小鼠。我们已经评估了重组小鼠白细胞介素12 （rmIL-12）的作用，它是干扰素γ (ifn - γ)的有效诱导剂和Th1 T细胞发育的启动子，在过继转移EAE的过程中。将从蛋白脂蛋白（PLP）启动的动物中分离的淋巴结细胞（LNC）转移并在体外用PLP刺激幼稚小鼠，导致进行性麻痹疾病，最终导致大多数受体完全后肢瘫痪。当小鼠注射在rmIL-12存在的情况下，体外用PLP刺激的LNC时，随后的病程更加严重和延长。与单独使用PLP刺激的LNC相比，在PLP体外刺激期间添加rmIL-12导致上清中ifn - γ增加10倍，肿瘤坏死因子(TNF) α增加2倍。然而，在体外用特异性抗体中和ifn - γ或tnf - α并不能消除rmIL-12加重后续疾病的能力。同样，在体内用rmIL-12处理的小鼠在抗原刺激的LNC转移后，与用载体处理的对照动物相比，出现了更严重和更长的病程。相比之下，在细胞移植后用小鼠IL-12抗体治疗小鼠，完全防止了瘫痪，只有40%的小鼠出现轻度疾病。这些结果表明，在体外用PLP和rmIL-12刺激抗原引物LNC可增强其随后的致脑性。此外，在LNC转移后体内抑制内源性IL-12可防止瘫痪，这表明内源性IL-12在这种自身免疫性疾病模型的发病机制中起关键作用。
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that can be transferred to naive mice via CD4+ T cells isolated from appropriately immunized mice. We have evaluated the effects of recombinant murine interleukin 12 (rmIL-12), a potent inducer of interferon gamma (IFN-gamma) and promoter of Th1 T cell development, on the course of adoptively transferred EAE. The transfer of lymph node cells (LNC) isolated from proteolipid protein (PLP)-primed animals and stimulated in vitro with PLP to naive mice resulted in a progressive paralytic disease culminating in complete hind limb paralysis in the majority of the recipients. When mice were injected with LNC that had been stimulated in vitro with PLP in the presence of rmIL-12, the subsequent course of disease was more severe and prolonged. The addition of rmIL-12 during the in vitro stimulation with PLP resulted in a 10-fold increase in IFN-gamma and a 2-fold increase in tumor necrosis factor (TNF) alpha in the supernatants, relative to LNC stimulated with PLP alone. However, neutralization of IFN-gamma or TNF-alpha in vitro with specific antibodies did not abrogate the ability of rmIL-12 to exacerbate the subsequent disease. Similarly, mice treated with rmIL-12 in vivo after the transfer of antigen-stimulated LNC developed a more severe and prolonged course of disease compared with vehicle-treated control animals. In contrast, treatment of mice with an antibody to murine IL-12 after cell transfer completely prevented paralysis, with only 40% of the mice developing mild disease. These results demonstrate that in vitro stimulation of antigen primed LNC with PLP and rmIL-12 enhances their subsequent encephalitogenicity. Furthermore, inhibition of endogenous IL-12 in vivo after LNC transfer prevented paralysis, suggesting that endogenous IL-12 plays a pivotal role in the pathogenesis of this model of autoimmune disease.