TRANSIENT HUMAN GENE-THERAPY - A NOVEL CYTOKINE REGULATORY STRATEGY FOR EXPERIMENTAL PANCREATITIS

Citation
W. Denham et al., TRANSIENT HUMAN GENE-THERAPY - A NOVEL CYTOKINE REGULATORY STRATEGY FOR EXPERIMENTAL PANCREATITIS, Annals of surgery, 227(6), 1998, pp. 812-819
Citations number
40
Categorie Soggetti
Surgery
Journal title
ISSN journal
00034932
Volume
227
Issue
6
Year of publication
1998
Pages
812 - 819
Database
ISI
SICI code
0003-4932(1998)227:6<812:THG-AN>2.0.ZU;2-U
Abstract
Objective The purpose of this study was to evaluate the ability to tra nsfect a murine pancreas with a human cytokine regulatory gene (interl eukin-10 [1L-10]) and examine the duration of transgene expression, it s effect on the normal pancreas, and its antiinflammatory effect durin g acute pancreatitis. Summary Background Data Interleukin-1 beta and t umor necrosis factor-alpha are known detrimental mediators during the progression of acute pancreatitis, and blockade of either cytokine res ults in decreased severity of pancreatitis and improved survival. Alth ough gene therapy has been proposed as a method to deliver protein-bas ed therapy during a number of conditions, no means of effectively tran sfecting the pancreas without inducing injury has been developed. Meth ods A plasmid-human IL-10 construct (pMP6-hlL-10) complexed with catio nic liposomes was administered by single intrapenitoneal injection to healthy mice. Effective transfection (reverse transcriptase-polymerase chain reaction for hIL-10 mRNA), transfected cell type (in situ polym erase chain reaction for hIL-10 DNA), and the effect on the normal pan creas were determined. Additional animals were transfected to determin e the effects of this regulatory gene on the severity of pancreatitis. Results Nearly 80% of all pancreatic cells expressed human DNA that w as subsequently transcribed into mRNA through day 14. The transfection event had no effect on amylase, lipase, or pancreatic histologic appe arance. Successful transfection could attenuate subsequently induced p ancreatitis (all parameters p < 0.05). Conclusions Transient transfect ion of a human IL-10 gene can be accomplished into all cell types of m urine pancreata using a plasmid/liposome vector, The DNA is effectivel y transcribed into intact mRNA and does not cause inflammation or acin ar cell damage. Transfer of this cytokine regulatory gene decreases th e severity of pancreatitis, demonstrating a benefit of gene therapy du ring this acute inflammatory process.