Mottram P L, Murray-Segal L J, Han W, Maguire J, Stein-Oakley A, Mandel T E
Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Diabetes. 1998 Sep;47(9):1399-405. doi: 10.2337/diabetes.47.9.1399.
Spontaneously diabetic nonobese diabetic (NOD/Lt) mice were treated with anti-T-cell monoclonal antibodies (mAbs) at the time of grafting with vascularized segmental pancreas isografts. Recipients were either untreated or given anti-CD4 and/or anti-CD8 mAbs (0.5 mg/20-g mouse on each of 4 consecutive days), which reduced target cell levels to <5% of normal. Graft function was monitored by measuring blood glucose (BG) levels. Transplants were removed for histological examination when BG returned to >20 mmol/l for two consecutive readings. Isografts from 3- to 4-week-old prediabetic mice placed in untreated diabetic NOD mice ceased functioning in 9-13 days with a mean survival time (MST) +/- SD of 10 +/- 2. Treatment with anti-CD4 prolonged survival significantly (MST = 61 +/- 35 days, P < 0.05 compared with untreated control mice). Anti-CD8 treatment was less effective, but it still significantly improved graft survival (MST = 24 +/- 9 days, P < 0.05 compared with untreated control mice). Anti-CD8 plus anti-CD4 treatment was highly effective in inhibiting autoimmune destruction of the grafts (MST = 97 +/- 8 days). This clearly demonstrates that transient inactivation of most T-cells with anti-CD4 plus anti-CD8 mAbs effectively controls autoimmune disease in the isograft, despite recovery of CD4 and CD8 T-cells to normal levels. Although insulitis developed in the long-term grafts, insulitis scores did not increase between 33 and 100 days, and none of the mice progressed to IDDM in 100 days. Histology showed a predominantly peri-islet T-cell and macrophage infiltrate with ductal expression of the cytokines interleukin (IL)-4, IL-2, and interferon-gamma. There was little infiltrate or expression of cytokines within the islets. Thus, mAb treatment at the time of grafting allowed isograft survival and prevented progression from insulitis to beta-cell destruction.
在将血管化节段性胰腺同基因移植物移植给自发糖尿病的非肥胖糖尿病（NOD/Lt）小鼠时，用抗T细胞单克隆抗体（mAb）对其进行治疗。受体小鼠要么不接受治疗，要么给予抗CD4和/或抗CD8 mAb（每只20克重的小鼠连续4天每天给予0.5毫克），这可将靶细胞水平降低至正常水平的<5%。通过测量血糖（BG）水平来监测移植物功能。当BG连续两次读数恢复到>20 mmol/l时，取出移植物进行组织学检查。将3至4周龄的糖尿病前期小鼠的同基因移植物植入未经治疗的糖尿病NOD小鼠体内，移植物在9至13天内停止功能，平均存活时间（MST）±标准差为10±2天。用抗CD4治疗可显著延长存活时间（MST = 61±35天，与未治疗的对照小鼠相比，P < 0.05）。抗CD8治疗效果较差，但仍能显著提高移植物存活率（MST = 24±9天，与未治疗的对照小鼠相比，P < 0.05）。抗CD8加抗CD4治疗在抑制移植物的自身免疫破坏方面非常有效（MST = 97±8天）。这清楚地表明，尽管CD4和CD8 T细胞恢复到正常水平，但用抗CD4加抗CD8 mAb使大多数T细胞短暂失活可有效控制同基因移植物中的自身免疫疾病。尽管长期移植物中出现了胰岛炎，但在33至100天之间胰岛炎评分并未增加，且在100天内没有一只小鼠发展为胰岛素依赖型糖尿病（IDDM）。组织学显示主要是胰岛周围T细胞和巨噬细胞浸润，细胞因子白细胞介素（IL）-4、IL-2和干扰素-γ在导管中表达。胰岛内几乎没有浸润或细胞因子表达。因此，在移植时进行mAb治疗可使同基因移植物存活，并防止从胰岛炎发展为β细胞破坏。
