School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, Guy's Hospital, London, United Kingdom.
UCB Pharma Ltd, Slough, United Kingdom.
Sci Rep. 2018 Sep 20;8(1):14106. doi: 10.1038/s41598-018-32546-4.
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.
自身免疫性疾病的抗原特异性免疫治疗目前仍然是唯一潜在的治愈方法。然而，将有前途的临床前研究结果转化为成功的临床应用已被证明具有挑战性。部分原因是由于 MHC II 的差异，必须重新设计用于人类应用的小鼠模型中的临床前发现。为了缩小临床前和临床研究之间的差距，我们创建了一种新型小鼠模型，该模型表达人类 HLA-DR4，但抗原呈递细胞中没有内源性 MHC。此外，人类 B7.1（CD80）在胰岛中受大鼠胰岛素启动子的控制下表达。尽管该模型不会自发发生糖尿病，但在佐剂中用源自鼠胰岛素原-2 的重叠肽挑战小鼠后，它易患 1 型糖尿病。与自发性 1 型糖尿病的 NOD 模型不同，但与人类疾病相似，该模型没有性别偏见。此外，与人类疾病相似，该疾病的特征是胰岛中有多种白细胞浸润，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 型糖尿病的详细了解，预计在研究转化、抗原特异性免疫治疗中的作用机制时将非常有用。
