Merani S, Edgar R L, Toso C, Emamaullee J, Thiesen A, Shapiro A M J
Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
Autoimmunity. 2009 Mar;42(3):242-8. doi: 10.1080/08916930802587950.
Protein kinase C (PKC) is an important signaling enzyme in the activation and regulation of T lymphocytes. T-cell-mediated destruction of beta-cells is a characteristic feature of autoimmune (Type 1) diabetes. Here we explore the ability of PKC inhibition, using the PKC inhibitor AEB-071 (AEB), to reduce disease in two animal models of spontaneous autoimmune diabetes (non-obese diabetic (NOD) mouse and biobreeding rat (BB)). NOD mice were treated with AEB for 4 weeks, starting at either 4 weeks of age (prior to the development of insulitis) or at 8 weeks of age, once insulitis is present. Animals treated with AEB during the effector phase of the disease (treatment onset at 8 weeks of age), showed a 2-week delay in diabetes onset (p < 0.05). In these animals, the extent of insulitis was lower than in vehicle-treated controls; however, neither serum autoimmune anti-GAD65 antibody levels nor pancreatic insulin content were different between experimental groups. Overall, inhibition of PKC can mildly reduce lymphocytic infiltrate of pancreatic islets and modestly delay onset of autoimmune diabetes in NOD mice. AEB, a T-cell-targeted immunosuppressive strategy, is only sufficient as a monothereapy to modestly delay onset of autoimmune disease in the NOD mouse.
蛋白激酶C（PKC）是T淋巴细胞激活和调节过程中的一种重要信号酶。T细胞介导的β细胞破坏是自身免疫性（1型）糖尿病的一个特征。在此，我们利用PKC抑制剂AEB - 071（AEB）探讨PKC抑制在两种自发性自身免疫性糖尿病动物模型（非肥胖糖尿病（NOD）小鼠和生物繁殖大鼠（BB））中减轻疾病的能力。NOD小鼠从4周龄（胰岛炎发生之前）或8周龄（胰岛炎出现后）开始用AEB治疗4周。在疾病效应期接受AEB治疗的动物（8周龄开始治疗），糖尿病发病延迟了2周（p < 0.05）。在这些动物中，胰岛炎的程度低于载体处理的对照组；然而，实验组之间血清自身免疫性抗GAD65抗体水平和胰腺胰岛素含量均无差异。总体而言，PKC抑制可轻度减少NOD小鼠胰岛的淋巴细胞浸润，并适度延迟自身免疫性糖尿病的发病。AEB作为一种针对T细胞的免疫抑制策略，仅作为单一疗法足以适度延迟NOD小鼠自身免疫性疾病的发病。
