title: Intramuscular delivery of a naked DNA plasmid encoding proinsulin and pancreatic regenerating III protein ameliorates type 1 diabetes mellitus.
abstract: Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of β 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 β 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-κB 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 β cells, which might be served as a promising candidate for the gene therapy of T1DM.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wen-Rui
authors.initials: WR
authors.lastname: Hou
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Xie
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Wang
authors.forename: Yu-Yong
authors.initials: YY
authors.lastname: Su
authors.forename: Jing-Li
authors.initials: JL
authors.lastname: Lu
authors.forename: Lu-Lu
authors.initials: LL
authors.lastname: Li
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Xiang
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy; D006943:Hyperglycemia / Q000628:therapy; D007273:Injections, Intramuscular; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D011384:Proinsulin / Q000235:genetics* / Q000627:therapeutic use; D011506:Proteins / Q000235:genetics* / Q000627:therapeutic use; D013311:Streptozocin; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology
chemical_list: D007328:Insulin; D011506:Proteins; C088549:RegIII protein, mouse; D013311:Streptozocin; D004247:DNA; D011384:Proinsulin