Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes
Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes
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DOI：
10.1073/pnas.0505497102
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发表时间：
2005-08-16
影响因子：
11.1
通讯作者：
Honjo, T
中科院分区：
文献类型：
--
作者：
Wang, J;Yoshida, T;Honjo, T
程序性细胞死亡1（PD-1，Pdcd 1）是一种属于CD 28/细胞毒性T淋巴细胞相关抗原-4家族的免疫抑制性受体，其缺陷小鼠分别在C57 BL/6和BALB/c背景下自发发生狼疮样自身免疫性疾病和自身免疫性扩张型心肌病。然而，PD-1缺陷如何在这两种菌株上诱导不同形式的自身免疫性疾病尚不清楚。在这里，我们报告说，PD-1缺乏症特别加速NOD（非肥胖糖尿病）小鼠I型糖尿病的发病和频率，T细胞浸润到胰岛中的强辅助T细胞1极化。这些结果表明，PD-1缺陷加速了背景菌株的自身免疫易感性，导致根据菌株的遗传背景诱导不同形式的自身免疫性疾病。以NOD-Pdcd 1（-/-）小鼠作为有效的I型糖尿病动物模型，通过遗传连锁分析筛选糖尿病易感基因位点。NOD-Pdcd 1（-/-）小鼠的糖尿病发病率受5个遗传基因座控制，包括3个已知的隐性基因座[Idd（胰岛素依赖型糖尿病）1、Idd 17和Idd 20]和2个先前未鉴定的显性基因座[Iddp（PD-1缺陷下的Idd）1和Iddp 2]。
Mice deficient in programmed cell death 1 (PD-1, Pdcd1), an immunoinhibitory receptor belonging to the CD28/cytotoxic T lymphocyte-associated antigen-4 family, spontaneously develop lupus-like autoimmune disease and autoimmune dilated cardiomyopathy on C57BL/6 and BALB/c backgrounds, respectively. However, how PD-1 deficiency induces different forms of autoimmune diseases on these two strains was unknown. Here, we report that PD-1 deficiency specifically accelerates the onset and frequency of type I diabetes in NOD (nonobese diabetic) mice, with strong T helper 1 polarization of T cells infiltrating into islets. These results suggest that PD-1 deficiency accelerates autoimmune predisposition of the background strain, leading to the induction of different forms of autoimmune diseases depending on the genetic background of the strain. Using NOD-Pdcd1(-/-) mice as an efficient animal model of type I diabetes, we screened diabetes-susceptible loci by genetic linkage analysis. The diabetic incidence of NOD-Pdcd1(-/-) mice was controlled by five genetic loci, including three known recessive loci [Idd (insulin-dependent diabetes) 1, Idd17, and Idd20] and two previously unidentified dominant loci [Iddp (Idd under PD-1 deficiency) 1 and Iddp2].