TGFβ plasmid construction and delivery for the prevention of type 1 diabetes

Leejin Park, Eunjig Lee, Sangkyung Lee, Minsu Lim, Hekyung Hong, Geewook Shin, Yongsoo Park

Research output: Chapter in Book/Report/Conference proceedingConference contribution

7 Citations (Scopus)

Abstract

Studies of animals with spontaneous autoimmune diabetes have revealed that autoreactive T cells that mediate islet β cell destruction can be manipulated by the administration of Th2 cytokines. Using gene delivery to express the targeted protein, we can overcome the need for frequent administration of cytokines on account of their short half-lives. In this study, the effect of hTGFβ gene delivery was evaluated both in vitro and in vivo using an adenovirus vector (Ad) constructed with an hTGFβ cDNA. In vitro transfection assays of the construct in HepG2, β cell lines, and islets showed good expression levels of hTGFβ and activation of smad3. Ad-hTGFβ enhanced differentiation and proliferation in the β cell line or islets without causing apoptosis. Of interest, Ad-hTGFβ transduction in CD4+CD25- T cells resulted in a significant enhanced expression of CD25 and a regulatory T cell-specific transcription factor, Foxp3. To evaluate in vivo efficacy, Ad-hTGFβ was intravenously injected into 7-week-old NOD mice and compared to the transduction using the vector only. The Ad-hTGFβ group had persistent gene expression for longer than 5 weeks, and high TGFβ serum level was secreted. There was no difference in the degree of insulitis between the Ad-hTGFβ group and controls. Although we found favorable in vitro results, such as decrease in islet apoptosis, enhanced proliferation and differentiation, and increase in the level of CD4 +CD25+ regulatory T cells, there was no difference in reduction of the development of T1D between controls and Ad-hTGFβ-injected mice. Nevertheless, if we find the appropriate mode and timing of TGFβ gene transduction, Ad-hTGFβ gene therapy might be useful in therapeutic cytokine delivery for the treatment of T1D.

Original languageEnglish
Title of host publicationImmunology of Diabetes V From Bench to Bedside
PublisherBlackwell Publishing Inc.
Pages177-182
Number of pages6
ISBN (Print)9781573317337
DOIs
Publication statusPublished - 2008 Dec

Publication series

NameAnnals of the New York Academy of Sciences
Volume1150
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Fingerprint

T-cells
Medical problems
Type 1 Diabetes Mellitus
Plasmids
Regulatory T-Lymphocytes
Cytokines
Genes
Apoptosis
T-Lymphocytes
Cell Line
Inbred NOD Mouse
Cells
Hep G2 Cells
Islets of Langerhans
Adenoviridae
Gene therapy
Genetic Therapy
Transfection
Transcription Factors
Complementary DNA

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Park, L., Lee, E., Lee, S., Lim, M., Hong, H., Shin, G., & Park, Y. (2008). TGFβ plasmid construction and delivery for the prevention of type 1 diabetes. In Immunology of Diabetes V From Bench to Bedside (pp. 177-182). (Annals of the New York Academy of Sciences; Vol. 1150). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1447.017
Park, Leejin ; Lee, Eunjig ; Lee, Sangkyung ; Lim, Minsu ; Hong, Hekyung ; Shin, Geewook ; Park, Yongsoo. / TGFβ plasmid construction and delivery for the prevention of type 1 diabetes. Immunology of Diabetes V From Bench to Bedside. Blackwell Publishing Inc., 2008. pp. 177-182 (Annals of the New York Academy of Sciences).
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Park, L, Lee, E, Lee, S, Lim, M, Hong, H, Shin, G & Park, Y 2008, TGFβ plasmid construction and delivery for the prevention of type 1 diabetes. in Immunology of Diabetes V From Bench to Bedside. Annals of the New York Academy of Sciences, vol. 1150, Blackwell Publishing Inc., pp. 177-182. https://doi.org/10.1196/annals.1447.017

TGFβ plasmid construction and delivery for the prevention of type 1 diabetes. / Park, Leejin; Lee, Eunjig; Lee, Sangkyung; Lim, Minsu; Hong, Hekyung; Shin, Geewook; Park, Yongsoo.

Immunology of Diabetes V From Bench to Bedside. Blackwell Publishing Inc., 2008. p. 177-182 (Annals of the New York Academy of Sciences; Vol. 1150).

Research output: Chapter in Book/Report/Conference proceedingConference contribution

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N2 - Studies of animals with spontaneous autoimmune diabetes have revealed that autoreactive T cells that mediate islet β cell destruction can be manipulated by the administration of Th2 cytokines. Using gene delivery to express the targeted protein, we can overcome the need for frequent administration of cytokines on account of their short half-lives. In this study, the effect of hTGFβ gene delivery was evaluated both in vitro and in vivo using an adenovirus vector (Ad) constructed with an hTGFβ cDNA. In vitro transfection assays of the construct in HepG2, β cell lines, and islets showed good expression levels of hTGFβ and activation of smad3. Ad-hTGFβ enhanced differentiation and proliferation in the β cell line or islets without causing apoptosis. Of interest, Ad-hTGFβ transduction in CD4+CD25- T cells resulted in a significant enhanced expression of CD25 and a regulatory T cell-specific transcription factor, Foxp3. To evaluate in vivo efficacy, Ad-hTGFβ was intravenously injected into 7-week-old NOD mice and compared to the transduction using the vector only. The Ad-hTGFβ group had persistent gene expression for longer than 5 weeks, and high TGFβ serum level was secreted. There was no difference in the degree of insulitis between the Ad-hTGFβ group and controls. Although we found favorable in vitro results, such as decrease in islet apoptosis, enhanced proliferation and differentiation, and increase in the level of CD4 +CD25+ regulatory T cells, there was no difference in reduction of the development of T1D between controls and Ad-hTGFβ-injected mice. Nevertheless, if we find the appropriate mode and timing of TGFβ gene transduction, Ad-hTGFβ gene therapy might be useful in therapeutic cytokine delivery for the treatment of T1D.

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Park L, Lee E, Lee S, Lim M, Hong H, Shin G et al. TGFβ plasmid construction and delivery for the prevention of type 1 diabetes. In Immunology of Diabetes V From Bench to Bedside. Blackwell Publishing Inc. 2008. p. 177-182. (Annals of the New York Academy of Sciences). https://doi.org/10.1196/annals.1447.017