Mangada Julie, Pearson Todd, Brehm Michael A, Wicker Linda S, Peterson Laurence B, Shultz Leonard D, Serreze David V, Rossini Aldo A, Greiner Dale L
Program in Immunology and Virology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Diabetes. 2009 Jan;58(1):165-73. doi: 10.2337/db08-0275. Epub 2008 Nov 4.
NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade-based tolerance protocols have failed in prolonging islet allograft survival in NOD mice.
To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes.
The frequency of diabetes is reduced in NOD.B6 Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD x CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2(g7) x CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival.
Il2 is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.
非肥胖糖尿病（NOD）小鼠可模拟人类1型糖尿病，用于研究自身免疫环境下胰岛移植的耐受诱导方案。然而，基于共刺激阻断的耐受方案未能延长NOD小鼠胰岛同种异体移植的存活时间。
为探究潜在机制，我们研究了共刺激阻断在携带降低糖尿病发生率的胰岛素依赖型糖尿病（Idd）基因座的同源NOD小鼠中延长胰岛同种异体移植存活时间的能力。
NOD.B6 Idd3小鼠的糖尿病发生率降低，而NOD.B6/B10 Idd3 Idd5小鼠几乎不发生糖尿病。与NOD小鼠相比，接受共刺激阻断治疗的NOD.B6 Idd3小鼠的胰岛同种异体移植存活时间延长，而在NOD.B6/B10 Idd3 Idd5小鼠中，胰岛同种异体移植存活时间与C57BL/6小鼠相似。相反，一些Idd基因座对移植耐受的诱导并无益处。与接受相同治疗的（C57BL/6.H2(g7)×CBA）F1小鼠相比，接受共刺激阻断治疗的（NOD×CBA）F1小鼠中同种异体反应性CD8 T细胞的清除受到损害。向接受共刺激阻断治疗的NOD小鼠注射外源性白细胞介素（IL）-2可延长胰岛同种异体移植的存活时间。接受共刺激阻断治疗的NOD.B6 Idd3小鼠清除了同种异体反应性CD8 T细胞，并表现出延长的胰岛同种异体移植存活时间。
Il2是Idd3糖尿病易感基因，可影响共刺激阻断治疗小鼠中T细胞清除的结果及胰岛同种异体移植的存活时间。这些数据表明，Idd基因座可通过共刺激阻断促进移植耐受的诱导，且IL-2/Idd3是这一过程中的关键组成部分。
