Gordon Ethel J, Wicker Linda S, Peterson Laurence B, Serreze David V, Markees Thomas G, Shultz Leonard D, Rossini Aldo A, Greiner Dale L, Mordes John P
University of Massachusetts Medical School, Diabetes Division, Department of Medicine, 373 Plantation St., Biotech 2, Suite 218, Worcester, MA 01605, USA.
Diabetes. 2005 Jan;54(1):107-15. doi: 10.2337/diabetes.54.1.107.
Costimulation blockade induces prolonged rat islet and skin xenograft survival in C57BL/6 mice. Nonobese diabetic (NOD) mice, which are used to model human autoimmune diabetes, are resistant to costimulation blockade-induced allograft tolerance. We tested the hypothesis that NOD mice would also be resistant to costimulation blockade-induced rat xenograft tolerance. We report that rat islet xenograft survival is short in spontaneously diabetic NOD mice treated with a tolerizing regimen of donor-specific transfusion and anti-CD154 antibody. Rat islet xenograft survival is only marginally longer in chemically diabetic NOD mice treated with costimulation blockade but is prolonged further in NOD Idd congenic mice bearing C57-derived chromosome 3 loci. Reciprocally, the presence of NOD-derived chromosome 3 loci shortens islet xenograft survival in tolerized C57BL/6 mice. Islet xenograft survival is longer in tolerized NOD.CD4a(-/-) and (NOD x C57BL/6)F1 mice than in NOD mice but still much shorter than in C57BL/6 mice. Skin xenograft survival in (NOD x C57BL/6)F1 mice treated with costimulation blockade is short, suggesting a strong genetic resistance to skin xenograft tolerance induction. We conclude that the resistance of NOD mice to xenograft tolerance induction involves some mechanisms that also participate in the expression of autoimmunity and other mechanisms that are distinct.
共刺激阻断可延长C57BL/6小鼠体内大鼠胰岛和皮肤异种移植物的存活时间。非肥胖糖尿病（NOD）小鼠常用于模拟人类自身免疫性糖尿病，对共刺激阻断诱导的同种异体移植耐受具有抗性。我们检验了NOD小鼠对共刺激阻断诱导的大鼠异种移植耐受也具有抗性这一假说。我们报告，在用供体特异性输血和抗CD154抗体的耐受方案治疗的自发性糖尿病NOD小鼠中，大鼠胰岛异种移植物的存活时间较短。在用共刺激阻断治疗的化学性糖尿病NOD小鼠中，大鼠胰岛异种移植物的存活时间仅略长，但在携带C57来源的3号染色体位点的NOD Idd同源基因小鼠中进一步延长。相反，NOD来源的3号染色体位点的存在会缩短耐受的C57BL/6小鼠中胰岛异种移植物的存活时间。在耐受的NOD.CD4a(-/-)和（NOD×C57BL/6）F1小鼠中，胰岛异种移植物的存活时间比NOD小鼠长，但仍比C57BL/6小鼠短得多。在用共刺激阻断治疗的（NOD×C57BL/6）F1小鼠中，皮肤异种移植物的存活时间较短，表明对皮肤异种移植耐受诱导具有很强的遗传抗性。我们得出结论，NOD小鼠对异种移植耐受诱导的抗性涉及一些也参与自身免疫表达的机制以及其他一些不同的机制。
