Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice.
Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice.
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DOI：
10.1084/jem.179.1.305
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发表时间：
1994-01-01
期刊：
影响因子：
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通讯作者：
Howard M
中科院分区：
文献类型：
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作者：
Ishida H;Muchamuel T;Sakaguchi S;Andrade S;Menon S;Howard M
我们先前已表明，对BALB/c小鼠持续给予抗白细胞介素10（抗 - IL - 10）抗体可改变自身抗体、肿瘤坏死因子α（TNF - α）和干扰素γ的内源性水平，这三种免疫介质已知会影响“易患狼疮”的新西兰黑/白（NZB/W）F1小鼠自身免疫的发展。为了探究在NZB/W F1小鼠中中和IL - 10的后果，从出生到8 - 10个月龄，每周给动物注射2 - 3次抗 - IL - 10抗体或同型对照抗体。通过总体存活率，或蛋白尿、肾小球肾炎或自身抗体的产生来监测，抗 - IL - 10治疗显著延迟了NZB/W F1小鼠自身免疫的发病。与Ig同型处理的对照组相比，抗 - IL - 10处理的小鼠在9个月时的存活率从10%提高到80%。这种对自身免疫的保护作用似乎是由于抗 - IL - 10诱导的内源性TNF - α上调，因为当在30周时与抗 - IL - 10治疗一起引入中和抗 - TNF - α抗体时，抗 - IL - 10保护的NZB/W F1小鼠迅速发生自身免疫。与这些实验中抗 - IL - 10治疗的保护作用一致，从4周龄到38周龄持续给予IL - 10加速了NZB/W F1小鼠自身免疫的发病。在正常的BALB/c小鼠中，相同时间段的持续给予IL - 10似乎没有毒性，也没有导致狼疮样自身免疫的发生。这些数据表明，IL - 10拮抗剂可能对人类系统性红斑狼疮的治疗有益。
We have previously shown that continuous administration of anti- interleukin 10 (anti-IL-10) antibodies (Abs) to BALB/c mice modifies endogenous levels of autoantibodies, tumor necrosis factor alpha (TNF- alpha), and interferon gamma, three immune mediators known to affect the development of autoimmunity in "lupus-prone" New Zealand black/white (NZB/W)F1 mice. To explore the consequences of IL-10 neutralization in NZB/W F1 mice, animals were injected two to three times per week from birth until 8-10 mo of age with anti-IL-10 Abs or with isotype control Abs. Anti-IL-10 treatment substantially delayed onset of autoimmunity in NZB/W F1 mice as monitored either by overall survival, or by development of proteinuria, glomerulonephritis, or autoantibodies. Survival at 9 mo was increased from 10 to 80% in anti- IL-10-treated mice relative to Ig isotype-treated controls. This protection against autoimmunity appeared to be due to an anti-IL-10- induced upregulation of endogenous TNF-alpha, since anti-IL-10- protected NZB/W F1 mice rapidly developed autoimmunity when neutralizing anti-TNF-alpha Abs were introduced at 30 wk along with the anti-IL-10 treatment. Consistent with the protective role of anti-IL-10 treatment in these experiments, continuous administration of IL-10 from 4 until 38 wk of age accelerated the onset of autoimmunity in NZB/W F1 mice. The same period of continuous IL-10 administration did not appear to be toxic to, or cause development of lupus-like autoimmunity in normal BALB/c mice. These data suggest that IL-10 antagonists may be beneficial in the treatment of human systemic lupus erythematosus.