Proinsulin-mediated induction of type 1 diabetes in HLA-DR4-transgenic mice.
Proinsulin-mediated induction of type 1 diabetes in HLA-DR4-transgenic mice.
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DOI：
10.1038/s41598-018-32546-4
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发表时间：
2018-09-20
影响因子：
4.6
通讯作者：
Peakman M
中科院分区：
文献类型：
--
作者：
Verhagen J;Smith EL;Whettlock EM;Macintyre B;Peakman M
自身免疫性疾病的抗原特异性免疫疗法目前仍是唯一有可能治愈的方法。然而，将有希望的临床前结果转化为成功的临床应用被证明是具有挑战性的。在一定程度上，这是因为由于MHC II的差异，小鼠模型中的临床前研究结果必须重新设计用于人类应用。为了缩小临床前研究和临床研究之间的差距，我们创造了一种新的小鼠模型，它在抗原呈递细胞上表达人类HLA-DR4，但不表达内源性MHC。此外，在大鼠胰岛素启动子的调控下，人B7.1(CD80)在胰岛表达。尽管该模型不会自发发展成糖尿病，但通过在佐剂中用来自小鼠胰岛素原-2的重叠多肽攻击小鼠，它很容易诱发1型糖尿病。与自发性1型糖尿病的NOD模型不同，但与人类的情况相似，该模型没有性别偏见。此外，与人类的情况相似，这种疾病的特点是胰岛有不同的白细胞渗透，并形成抗胰岛素原自身抗体。我们在这里报告的模型提供了对1型糖尿病的详细见解，并有望在研究转化性、抗原特异性免疫治疗的作用机制时被证明是有用的。
Antigen-specific immunotherapy of autoimmune disease currently remains the only potentially curative approach. However, translation of promising pre-clinical results into successful clinical application has proven challenging. In part, this is because pre-clinical findings in mouse models have to be redesigned for human application due to differences in MHC II. To reduce the gap between pre-clinical and clinical studies, we have created a novel mouse model that expresses human HLA-DR4, but no endogenous MHC on antigen-presenting cells. Moreover, human B7.1 (CD80) is expressed in the pancreatic islets under the control of the rat insulin promoter. Although this model does not develop diabetes spontaneously, it is susceptible to the induction of type 1 diabetes by challenging mice with overlapping peptides derived from murine proinsulin-2 in adjuvant. Unlike the NOD model of spontaneous type 1 diabetes, but akin to the human condition, this model does not have a gender bias. Furthermore, similar to the human condition, the disease is characterised by a diverse leucocyte infiltration of the pancreatic islets and the formation of anti-proinsulin auto-antibodies. The model that we report here offers detailed insights into type-1 diabetes and is expected to prove instrumental when studying the mechanism of action in translational, antigen-specific immunotherapy.
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影响因子：
16.6
作者：
Serr I;Fürst RW;Achenbach P;Scherm MG;Gökmen F;Haupt F;Sedlmeier EM;Knopff A;Shultz L;Willis RA;Ziegler AG;Daniel C
通讯作者：
Daniel C
影响因子：
8.6
作者：
Gebe, John A.;Unrath, Kellee A.;Nepom, Gerald T.
通讯作者：
Nepom, Gerald T.
人源化小鼠中 1 型糖尿病的诱导
DOI：
10.1073/pnas.1710415114
发表时间：
2017-10-10
影响因子：
11.1
作者：
Tan, Shulian;Li, Yang;Yang, Yong-Guang
通讯作者：
Yang, Yong-Guang
影响因子：
15.9
作者：
Wen, L;Chen, NY;Wong, FS
通讯作者：
Wong, FS
影响因子：
4.6
作者：
Willcox, A.;Richardson, S. J.;Morgan, N. G.
通讯作者：
Morgan, N. G.