Chaillous L, Darquy S, Maugendre S, Rivereau A S, Reach G, Saï P
Laboratory of Cellular and Molecular Immuno-Endocrinology associated with INRA/ENVN, University School of Medicine, Nantes, France.
Diabetologia. 1996 May;39(5):523-9. doi: 10.1007/BF00403298.
Non-obese diabetic (NOD) mice develop an autoimmune disease with a long prodromal period and constitute a model for investigating the prevention of human insulin-dependent diabetes mellitus. Since insulin injected prophylactically has been shown to reduce incidence of diabetes in NOD mice, we tested a new strategy consisting of prophylactic xenografts of porcine pancreatic islets immunoprotected in semipermeable hollow fibres. Female NOD mice were transplanted twice (at 60 and 180 days of age) with islet-containing or empty fibres. Within the group grafted with protected islets, the incidence of diabetes was reduced (37 vs 75%; p < 0.01), the onset of disease was delayed (p < 0.02), and the severity of lymphocytic inflammation of endogenous islets was reduced (p < 0.02). When already diabetic mice were not taken into account for analysis, blood glucose level was slightly lower in those grafted with islet-containing fibres (p < 0.04). Graft function was also evidenced by HPLC separation of porcine insulin in NOD sera. Histological and perifusion studies of fibres retrieved from recipients confirmed immunoprotection. During co-transfer, T splenocytes from mice grafted with islet-containing fibres were able to reduce the capacity of T cells from diabetic donors to adoptively transfer the disease (p < 0.01). Antigens for islet-cell autoantibodies (ICA) in pancreata from both groups were compared by immunofluorescence with the same ICA-positive human sera to ensure that differences were due to antigen quantitative changes. These antigens, which could serve as an index of a possibly more extensive antigen beta-cell rest, were decreased (p < 0.01) in mice grafted with protected islets. Reduction of diabetes and insulitis following early islet transplantation may thus be due to generation of cellular mechanisms that actively suppress disease, and possibly in part to a decrease in antigens which make beta cells less vulnerable to autoimmune aggression. These effects can be obtained with xenogeneic islets protected in hollow fibres, thereby eliminating the need for immunosuppression. Based on the concept of prophylactic insulin therapy, this form of insulin administration offers a controlled means of delivering insulin to meet the physiological needs of recipients.
非肥胖型糖尿病（NOD）小鼠会患上一种有很长前驱期的自身免疫性疾病，是研究人类胰岛素依赖型糖尿病预防的模型。由于预防性注射胰岛素已被证明可降低NOD小鼠的糖尿病发病率，我们测试了一种新策略，即对半透性中空纤维中免疫保护的猪胰岛进行预防性异种移植。雌性NOD小鼠在60日龄和180日龄时接受两次移植，移植含胰岛或不含胰岛的纤维。在移植了受保护胰岛的组中，糖尿病发病率降低（37%对75%；p<0.01），疾病发作延迟（p<0.02），内源性胰岛淋巴细胞炎症的严重程度降低（p<0.02）。在分析时不考虑已患糖尿病的小鼠，移植含胰岛纤维的小鼠血糖水平略低（p<0.04）。通过高效液相色谱法分离NOD血清中的猪胰岛素也证明了移植功能。对从受体中取出的纤维进行组织学和灌注研究证实了免疫保护作用。在共同移植过程中，移植含胰岛纤维的小鼠的T脾细胞能够降低糖尿病供体T细胞过继转移疾病的能力（p<0.01）。用相同的胰岛细胞自身抗体（ICA）阳性人血清通过免疫荧光比较两组胰腺中胰岛细胞自身抗体的抗原，以确保差异是由于抗原定量变化所致。这些抗原可作为可能更广泛的抗原β细胞静止的指标，在移植了受保护胰岛的小鼠中减少（p<0.01）。早期胰岛移植后糖尿病和胰岛炎的减轻可能是由于产生了积极抑制疾病的细胞机制，并且可能部分是由于使β细胞不易受到自身免疫攻击的抗原减少。这些作用可以通过在中空纤维中保护的异种胰岛获得，从而无需免疫抑制。基于预防性胰岛素治疗的概念，这种胰岛素给药形式提供了一种可控的方式来输送胰岛素以满足受体的生理需求。
