Islet allograft survival induced by costimulation blockade in NOD mice is controlled by allelic variants of Idd3
Islet allograft survival induced by costimulation blockade in NOD mice is controlled by allelic variants of Idd3
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DOI：
10.2337/diabetes.53.8.1972
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发表时间：
2004-08-01
期刊：
影响因子：
7.7
通讯作者：
Greiner, DL
中科院分区：
文献类型：
--
作者：
Pearson, T;Weiser, P;Greiner, DL
NOD小鼠发展为1型自身免疫性糖尿病，并表现出对移植耐受诱导的遗传优势抗性。这两种表型在基因上是可分离的。共刺激阻断不能延长（NOD X C57BL/6）F1小鼠和通过遗传引入保护性主要组织相容性复合体（MHC）或非MHC Idd区基因而产生糖尿病抵抗的NOD相关菌株的皮肤同种异体移植存活。在这里，我们验证了NOD小鼠对皮肤异体移植物耐受的遗传基础也适用于胰岛异体移植物的假设。令人惊讶的是，共刺激阻断在（NOD X C57BL/6）F1小鼠中诱导永久性胰岛移植存活，但在NOD小鼠中没有。共刺激阻断后，胰岛移植存活延长了糖尿病抵抗性NOD。B6 Idd3小鼠和无糖尿病C57BL/6小鼠的NOD Idd3变异缩短。胰岛异体移植耐受不能诱导糖尿病抵抗性NOD。B10 Idd5和NOD。B10 Idd9小鼠。结果表明：1)NOD小鼠对同种异体胰岛移植耐受诱导具有抵抗性；2)与皮肤异体移植不同，对胰岛异体移植耐受的抗性是一种遗传隐性性状；3) Idd3区域基因是诱导胰岛异体移植耐受的重要决定因素；4) Idd3抗性位点提高自身耐受性和诱导异源耐受性的机制可能存在重叠。
NOD mice develop type 1 autoimmune diabetes and exhibit genetically dominant resistance to transplantation tolerance induction. These two phenotypes are genetically separable. Costimulation blockade fails to prolong skin allograft survival in (NOD X C57BL/6)F1 mice and in NOD-related strains made diabetes-resistant by congenic introduction of protective major histocompatibility complex (MHC) or non-MHC Idd region genes. Here, we tested the hypothesis that the genetic basis for the resistance of NOD mice to skin allograft tolerance also applies to islet allografts. Surprisingly, costimulation blockade induced permanent islet allograft survival in (NOD X C57BL/6)F1 mice but not in NOD mice. After costimulation blockade, islet allograft survival was prolonged in diabetes-resistant NOD.B6 Idd3 mice and shortened in diabetes-free C57BL/6 mice congenic for the NOD Idd3 variant. Islet allograft tolerance could not be induced in diabetes-resistant NOD.B10 Idd5 and NOD.B10 Idd9 mice. The data demonstrate that 1) NOD mice resist islet allograft tolerance induction; 2) unlike skin allografts, resistance to islet allograft tolerance is a genetically recessive trait; 3) an Idd3 region gene(s) is an important determinant of islet allograft tolerance induction; and 4) there may be overlap in the mechanism by which the Idd3 resistance locus improves self-tolerance and the induction of allotolerance.