Intramuscular delivery of a naked DNA plasmid encoding proinsulin and pancreatic regenerating III protein ameliorates type 1 diabetes mellitus
Intramuscular delivery of a naked DNA plasmid encoding proinsulin and pancreatic regenerating III protein ameliorates type 1 diabetes mellitus
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肌内注射编码胰岛素原和胰腺再生 III 蛋白的裸 DNA 质粒可改善 1 型糖尿病
DOI：
10.1016/j.phrs.2010.12.009
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发表时间：
2011-04-01
影响因子：
9.3
通讯作者：
Xiang, Ming
中科院分区：
文献类型：
--
作者：
Hou, Wen-Rui;Xie, Sheng-Nan;Xiang, Ming
1型糖尿病（T1 DM）是一种自身免疫性疾病，其特征在于胰岛炎症和β细胞破坏。到目前为止，仍然没有治愈这种毁灭性疾病的方法，应该开发替代方法。为了探索一种新的结合免疫治疗和β细胞再生的基因治疗策略，我们构建了编码胰岛素原（PI）和胰腺再生（Reg）III蛋白（pReg/PI）的非病毒质粒。研究了该质粒对T1 DM的治疗潜力。肌肉注射pReg/PI可显著降低STZ诱导的T1 DM小鼠的高血糖和糖尿病发病率，并提高血清胰岛素含量。用pReg/PI处理也恢复了Th 1/Th 2细胞因子的平衡，并扩增了CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞，这可能是建立自身免疫耐受的原因。另外，与用空载体pBudCE 4.1（pBud）处理的小鼠相比，观察到通过抑制pReg/PI处理的小鼠的胰腺中NF-κ B的活化而实现的减轻的胰岛炎和细胞凋亡。这些结果表明，pReg/PI肌肉注射可通过重建自身免疫耐受和促进β细胞再生，明显改善STZ诱导的T1 DM，有望成为T1 DM基因治疗的候选药物。(C)2010爱思唯尔有限公司保留所有权利。
Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of beta cells. Up to now, there is still no cure for this devastating disease and alternative approach should be developed. To explore a novel gene therapy strategy combining immunotherapy and beta cell regeneration, we constructed a non-viral plasmid encoding proinsulin (PI) and pancreatic regenerating (Reg) III protein (pReg/PI). Therapeutic potentials of this plasmid for T1DM were investigated. Intramuscular delivery of pReg/PI resulted in a significant reduction in hyperglycemia and diabetes incidence, with an increased insulin contents in the serum of T1DM mice model induced by STZ. Treatment with pReg/PI also restored the balance of Th1/Th2 cytokines and expanded CD4(+)CD25(+)Foxp3(+) T regulatory cells, which may attribute to the establishment of self-immune tolerance. Additionally, in comparison to the mice treated with empty vector pBudCE4.1 (pBud), attenuated insulitis and apoptosis achieved by inhibiting activation of NF-kappa B in the pancreas of pReg/PI treated mice were observed. In summary, these results indicate that intramuscular delivery of pReg/PI distinctly ameliorated STZ-induced T1DM by reconstructing the immunological self-tolerance and promoting the regeneration of beta cells, which might be served as a promising candidate for the gene therapy of T1DM. (C) 2010 Elsevier Ltd. All rights reserved.