Drage Martin, Zaccone Paola, Phillips Jenny M, Nicoletti Ferdinando, Dawson Janet, Andrew Bradley J, Cooke Anne
Department of Pathology, University of Cambridge, United Kingdom.
Transplantation. 2002 Sep 15;74(5):611-9. doi: 10.1097/00007890-200209150-00005.
Successful islet transplantation in type 1 diabetes requires tolerance induction of both allo- and autoreactive T-cell responses. Monoclonal antibodies targeting the CD4 coreceptor on T-helper cells have been shown to be effective in this regard. In type 1 diabetes, there is some evidence to suggest that cytokines such as interleukin (IL)-1 may be involved in beta-cell destruction. The high glucose levels associated with type 1 diabetes are also known to be toxic to beta cells.
The tempo of T-cell and macrophage infiltration into syngeneic islets transplanted into diabetic nonobese diabetic (NOD) mice was examined by immunohistochemistry. We investigated the ability of a nondepleting anti-CD4 monoclonal antibody (YTS177) to induce tolerance to syngeneic islet grafts in female spontaneous diabetic NOD mice and in an adoptive transfer model of diabetes in NOD mice. The spontaneous model was used to test the effect on graft function of perioperative insulin therapy in mice treated with YTS177. The ability of soluble interleukin (sIL)-1 receptor (R) type II (sIL-1RII) to inhibit IL-1 effects in syngeneic islet transplants was also assessed.
Cellular infiltration of CD3 cells and macrophages into the islet graft coincided with loss of graft function in untreated mice. Self-tolerance to beta cells was restored with YTS177, allowing long-term graft survival in a proportion of animals. The use of perioperative insulin therapy increased the number of successful grafts in spontaneously diabetic NOD mice treated with YTS177. The combination of YTS177 with sIL-1RII significantly improved the rates of graft survival compared with graft survival in YTS177-treated spontaneously diabetic NOD mice.
Nondepleting anti-CD4 antibodies restore self tolerance to syngeneic islet transplants in diabetic NOD mice. Insulin therapy improves graft survival in mice treated with YTS177. Preventing the action of IL-1 greatly improves graft survival induced with YTS177.
1型糖尿病患者胰岛移植成功需要诱导对同种异体和自身反应性T细胞反应的耐受。靶向辅助性T细胞上CD4共受体的单克隆抗体在这方面已被证明是有效的。在1型糖尿病中，有证据表明细胞因子如白细胞介素（IL）-1可能参与β细胞破坏。与1型糖尿病相关的高血糖水平也已知对β细胞有毒性。
通过免疫组织化学检查T细胞和巨噬细胞浸润同基因胰岛移植到糖尿病非肥胖糖尿病（NOD）小鼠体内的时间进程。我们研究了一种非清除性抗CD4单克隆抗体（YTS177）在雌性自发性糖尿病NOD小鼠和NOD小鼠糖尿病过继转移模型中诱导对同基因胰岛移植耐受的能力。自发性模型用于测试围手术期胰岛素治疗对用YTS177治疗的小鼠移植功能的影响。还评估了可溶性白细胞介素（sIL）-1受体（R）II型（sIL-1RII）抑制同基因胰岛移植中IL-1作用的能力。
在未治疗的小鼠中，CD3细胞和巨噬细胞向胰岛移植的细胞浸润与移植功能丧失同时发生。YTS177恢复了对β细胞的自身耐受，使一部分动物的移植能够长期存活。围手术期胰岛素治疗的使用增加了用YTS177治疗的自发性糖尿病NOD小鼠成功移植的数量。与用YTS177治疗的自发性糖尿病NOD小鼠的移植存活相比，YTS177与sIL-1RII的联合显著提高了移植存活率。
非清除性抗CD4抗体恢复了糖尿病NOD小鼠对同基因胰岛移植的自身耐受。胰岛素治疗提高了用YTS177治疗的小鼠的移植存活率。阻止IL-1的作用大大提高了YTS177诱导的移植存活率。
