Thorens Bernard
Department of Physiology and Centre for Integrative Genomics, Génopode Building, Lausanne, Switzerland.
Swiss Med Wkly. 2007 Mar 2;137 Suppl 155:68S-71S.
Transplantation of insulin secreting cells is regarded as a possible treatment for type 1 diabetes. One major difficulty in this approach is, however, that the transplanted cells are exposed to the patient's inflammatory and autoimmune environment, which originally destroyed their own beta-cells. Therefore, even if a good source of insulin-secreting cells can be identified for transplantation therapy, these cells need to be protected against these destructive influences. The aim of this project was to evaluate, using a clonal mouse beta-cell line, whether genetic engineering of protective genes could be a viable option to allow these cells to survive when transplanted into autoimmune diabetic mice. We demonstrated that transfer of the Bcl-2 anti-apoptotic gene and of several genes specifically interfering with cytokines intracellular signalling pathways, greatly improved resistance of the cells to inflammatory stresses in vitro. We further showed that these modifications did not interfere with the capacity of these cells to correct hyperglycaemia for several months in syngeneic or allogeneic streptozocin-diabetic mice. However, these cells were not protected against autoimmune destruction when transplanted into type 1 diabetic NOD mice. This suggests that in addition to inflammatory attacks by cytokines, autoimmunity very efficiently kills the transplanted cells, indicating that multiple protective mechanisms are required for efficient transplantation of insulin-secreting cells to treat type 1 diabetes.
胰岛素分泌细胞移植被视为治疗1型糖尿病的一种可能方法。然而，这种方法的一个主要困难在于，移植的细胞会暴露于患者的炎症和自身免疫环境中，而正是这种环境最初破坏了他们自身的β细胞。因此，即使能够确定用于移植治疗的良好胰岛素分泌细胞来源，这些细胞也需要受到保护，免受这些破坏性影响。本项目的目的是使用克隆小鼠β细胞系评估，保护性基因的基因工程是否可能是一种可行的选择，以使这些细胞在移植到自身免疫性糖尿病小鼠体内时能够存活。我们证明，Bcl-2抗凋亡基因以及几个特异性干扰细胞因子细胞内信号通路的基因的转移，极大地提高了细胞在体外对炎症应激的抵抗力。我们进一步表明，这些修饰不会干扰这些细胞在同基因或异基因链脲佐菌素诱导的糖尿病小鼠中纠正高血糖数月的能力。然而，当将这些细胞移植到1型糖尿病NOD小鼠体内时，它们并未受到自身免疫破坏的保护。这表明，除了细胞因子的炎症攻击外，自身免疫非常有效地杀死了移植的细胞，这表明需要多种保护机制才能有效地移植胰岛素分泌细胞来治疗1型糖尿病。
