Mottram Patricia L, Murray-Segal Lisa J, Han Wenruo, Maguire Julie, Stein-Oakley Alicia N
The Austin Research Institute, Heidelberg, Victoria, Australia.
Transpl Immunol. 2002 Jun;10(1):63-72. doi: 10.1016/s0966-3274(02)00050-3.
Diabetes in NOD mice is an autoimmune disease similar to Type I diabetes in humans. Prior to hypoglycemia, changes in the islet infiltrate led to autoreactive T cell activation and destruction of the insulin-producing beta cells. If T cell activation can be inhibited before beta cell destruction is complete, islet cell rescue and regeneration can occur. Female NOD mice > 100 days old with blood glucose levels > 20 mM/l for less than 7 days were selected as 'recent onset' mice. Untreated, all of these animals would die of diabetes in < 40 days. Mice treated with anti-CD4 (GK1.5) achieved 14.3% permanent remission, while those treated with anti-CD8 (53.6.7) showed 33.3% permanent remission. Mice treated with anti-CD3 (145-2C1) also achieved 33.3% permanent remission, but 14% of these died of first dose syndrome. In mice treated with a low dose of anti-CD3 (10 microg KT3), which did not induce first dose syndrome, 50% remained in remission for > 100 days. This dose of mAb reduced insulitis but did not deplete splenic CD3 cells. When mice in remission were challenged with a vascularized pancreas isograft at 50 days, 9/22 remained normal and 13/22 had recurrent disease in both transplanted and native pancreas. Of the long-surviving isografts 7/9 were in KT3 treated recipients. Histology showed activated T cell infiltration in the native and transplanted pancreases of mice with transient remission. Benign insulitis with macrophages, B cells, CD4 > CD8 T cells and low levels of IL-2R, IL-2, IFN-gamma and IL-4 was seen in islets from the native pancreas and in long surviving pancreas isografts in mice that remained in remission. Thus, using low dose KT3, it was possible to halt the development of diabetes in 50% of animals treated soon after diagnosis, despite significant islet cell destruction at this stage. Of the KT3 treated mice in permanent remission, 70% had re-established tolerance to autoantigen and did not destroy vascularized pancreas isografts.
非肥胖糖尿病（NOD）小鼠的糖尿病是一种类似于人类I型糖尿病的自身免疫性疾病。在低血糖发生之前，胰岛浸润的变化会导致自身反应性T细胞活化以及产生胰岛素的β细胞被破坏。如果在β细胞破坏完全之前抑制T细胞活化，胰岛细胞就可以得到挽救并再生。选择100日龄以上、血糖水平>20 mM/l且持续时间少于7天的雌性NOD小鼠作为“近期发病”小鼠。未经治疗的情况下，所有这些动物会在40天内死于糖尿病。用抗CD4（GK1.5）治疗的小鼠实现了14.3%的永久缓解，而用抗CD8（53.6.7）治疗的小鼠显示出33.3%的永久缓解。用抗CD3（145-2C1）治疗的小鼠也实现了33.3%的永久缓解，但其中14%死于首剂综合征。在用低剂量抗CD3（10微克KT3）治疗的小鼠中，该剂量未诱发首剂综合征，50%的小鼠缓解超过100天。该剂量的单克隆抗体减少了胰岛炎，但未耗尽脾脏CD3细胞。当缓解期的小鼠在50天时接受血管化胰腺同种异体移植挑战时，22只中有9只保持正常，13只在移植胰腺和天然胰腺中均出现疾病复发。在长期存活的同基因移植中，9只中有7只移植给了接受KT3治疗的受体。组织学显示，短暂缓解的小鼠的天然胰腺和移植胰腺中有活化的T细胞浸润。在天然胰腺的胰岛以及缓解期小鼠长期存活的胰腺同种异体移植中，可见巨噬细胞、B细胞、CD4>CD8 T细胞以及低水平的IL-2R、IL-2、IFN-γ和IL-4构成的良性胰岛炎。因此，使用低剂量KT3，在诊断后不久治疗的50%的动物中有可能阻止糖尿病的发展，尽管在此阶段胰岛细胞已发生显著破坏。在实现永久缓解的接受KT3治疗的小鼠中，70%重新建立了对自身抗原的耐受性，并且不会破坏血管化胰腺同种异体移植。
