I-E+ nonobese diabetic mice develop insulitis and diabetes.
I-E+ nonobese diabetic mice develop insulitis and diabetes.
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DOI：
10.1084/jem.178.3.793
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发表时间：
1993-09-01
期刊：
影响因子：
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通讯作者：
Wicker LS
中科院分区：
文献类型：
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作者：
Podolin PL;Pressey A;DeLarato NH;Fischer PA;Peterson LB;Wicker LS
非肥胖糖尿病(NOD)小鼠I型糖尿病的发生受多基因控制，其中一个或多个基因与主要组织相容性复合体(MHC)相关。MHC II类区域与疾病的发展有关，在NOD小鼠中表达的I-E转基因被证明提供了对胰岛素炎和糖尿病的保护。为了检测表达I-E+或I-E-非NOD MHC对NOD背景的影响，我们培育了3个I-E+和3个I-E-NOD MHC同源菌株(分别为NOD.H-2I5、NOD.H-2k和NOD.H-2H2，以及NOD.H-2H4、NOD.H-2I7和NOD.H-2b)。在这些品系中，I-E+NOD.H-2h2和I-E-NOD.H-2H4小鼠都出现了岛炎，但没有糖尿病。其余四个同源菌株没有胰岛素炎和糖尿病。这些结果表明，在没有NOD MHC的情况下，糖尿病不会发生。每个NOD MHC同源品系与NOD品系杂交，产生I-E+和I-E-F1小鼠；这些小鼠在NOD背景上表达一剂NOD MHC和一剂非NOD MHC。虽然一次剂量的非NOD MHC为所有F1菌株提供了很大程度的疾病保护，但5-12个月龄的I-E+和I-E-F1小鼠出现了岛炎和环磷酰胺诱导的糖尿病。当I-E+F1小鼠在9-17mo龄时，也出现自发性糖尿病。这些数据首次证明I-E+NOD小鼠患上糖尿病，表明NOD小鼠I-E的表达本身不足以预防胰岛素炎或糖尿病。事实上，I-E-F1株并不比I-E+F1株对糖尿病的保护作用更强，这表明其他非NOD MHC连锁基因在预防疾病方面也很重要。最后，将NOD骨髓移植到接受照射的I-E+F1受体体内会导致糖尿病的高发病率，这表明在骨髓来源的细胞中没有表达的非NOD MHC产物在胸腺中的表达不足以提供对糖尿病的保护。
The development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E+ or I-E- non-NOD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congenic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E+ NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E- F1 strains were no more protected from diabetes than I-E+ F1 strains, suggesting that other non-NOD MHC- linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow- derived cells, is not sufficient to provide protection from diabetes.