Podolin P L, Pressey A, DeLarato N H, Fischer P A, Peterson L B, Wicker L S
Department of Autoimmune Diseases Research, Mercke Research Laboratories, Rahway, New Jersey 07065.
J Exp Med. 1993 Sep 1;178(3):793-803. doi: 10.1084/jem.178.3.793.
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.
非肥胖糖尿病（NOD）小鼠中I型糖尿病的发生受多个基因控制，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类区域与疾病发展有关，在NOD小鼠中表达I-E转基因可预防胰岛炎和糖尿病。为了研究在NOD背景下表达I-E+或I-E-非NOD MHC的影响，构建了三个I-E+和三个I-E- NOD MHC同源近交系（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+的NOD.H-2h2和I-E-的NOD.H-2h4小鼠均发生了胰岛炎，但未发生糖尿病。其余四个同源近交系未出现胰岛炎和糖尿病。这些结果表明，在没有NOD MHC的情况下，糖尿病不会发生。将每个NOD MHC同源近交系与NOD品系杂交，产生I-E+和I-E- F1小鼠；因此，这些小鼠在NOD背景下表达一剂NOD MHC和一剂非NOD MHC。虽然单剂量的非NOD MHC为所有F1品系提供了很大程度的疾病保护，但一部分5-12月龄的I-E+和I-E- F1小鼠发生了胰岛炎和环磷酰胺诱导的糖尿病。当I-E+ F1小鼠9-17月龄时，也出现了自发性糖尿病。这些数据首次证明I-E+的NOD小鼠会发生糖尿病，表明NOD小鼠中I-E的表达本身不足以预防胰岛炎或糖尿病。事实上，I-E- F1品系在预防糖尿病方面并不比I-E+ F1品系更具优势，这表明其他与非NOD MHC相关的基因在预防疾病方面很重要。最后，将NOD骨髓移植到经辐射的I-E+ F1受体中导致糖尿病的高发病率，这表明在骨髓来源细胞中不表达的情况下，胸腺中非NOD MHC产物的表达不足以预防糖尿病。
